U.S. patent application number 15/961236 was filed with the patent office on 2018-10-25 for peroxide formulations and methods and applicators for using the same.
The applicant listed for this patent is ACLARIS THERAPEUTICS, INC.. Invention is credited to Brian BEGER, Michael A. BOTTA, Marc Barry BROWN, Charles Rodney GREENAWAY EVANS, Sian Tiong LIM, Thomas NAGLER, Christopher PHILLIPS, Christopher POWALA, Stuart D. SHANLER.
Application Number | 20180303875 15/961236 |
Document ID | / |
Family ID | 54333109 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180303875 |
Kind Code |
A1 |
SHANLER; Stuart D. ; et
al. |
October 25, 2018 |
PEROXIDE FORMULATIONS AND METHODS AND APPLICATORS FOR USING THE
SAME
Abstract
Embodiments are directed to a stable composition comprising
stabilized hydrogen peroxide and 2-propanol and applicators
configured to store, dispense, and apply such stable compositions.
Such compositions may be used to treat skin conditions such as
warts, condyloma accuminatum, molluscum contagiosum, acrochordons,
seborrheic keratosis, or a combination thereof. Some embodiments
also describe take home compositions, in office compositions,
over-the-counter compositions, and kits for the use of such
compositions.
Inventors: |
SHANLER; Stuart D.;
(Malvern, PA) ; POWALA; Christopher; (Radnor,
PA) ; PHILLIPS; Christopher; (Doylestown, PA)
; BEGER; Brian; (Newtown, PA) ; GREENAWAY EVANS;
Charles Rodney; (Surrey, GB) ; LIM; Sian Tiong;
(Surrey, GB) ; BROWN; Marc Barry; (Watford
Hertfordshire, GB) ; BOTTA; Michael A.; (Ridge,
NY) ; NAGLER; Thomas; (Greenlawn, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ACLARIS THERAPEUTICS, INC. |
Wayne |
PA |
US |
|
|
Family ID: |
54333109 |
Appl. No.: |
15/961236 |
Filed: |
April 24, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15591894 |
May 10, 2017 |
9980983 |
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15961236 |
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14692665 |
Apr 21, 2015 |
9675639 |
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15591894 |
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61982217 |
Apr 21, 2014 |
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62085466 |
Nov 28, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 35/003 20130101;
A61P 35/00 20180101; A61K 8/22 20130101; A61K 8/34 20130101; A61K
2800/872 20130101; A61M 2205/7545 20130101; A61P 31/00 20180101;
A61K 47/10 20130101; A61P 17/12 20180101; A61P 17/00 20180101; A61Q
19/08 20130101; A61K 33/40 20130101; A61Q 19/00 20130101; A61K
9/0014 20130101; A61K 9/08 20130101 |
International
Class: |
A61K 33/40 20060101
A61K033/40; A61M 35/00 20060101 A61M035/00; A61K 8/22 20060101
A61K008/22; A61Q 19/08 20060101 A61Q019/08; A61Q 19/00 20060101
A61Q019/00; A61K 9/08 20060101 A61K009/08; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00; A61K 8/34 20060101
A61K008/34 |
Claims
1-50. (canceled)
51. A topical composition for treating a skin condition comprising
about 25% w/w to about 70% w/w stabilized hydrogen peroxide and an
alcohol in an amount of about 0.1% w/w to about 10% w/w.
52. The topical composition of claim 51, wherein the alcohol is a
primary alcohol, a secondary alcohol, a tertiary alcohol, or a
combination thereof.
53. The topical composition of claim 51, wherein the alcohol is
selected from methanol, ethanol, butanol, 1-propanol, pentanol,
hexanol, octanol, nonanol, decanol, 2-butanol, 2-propanol,
2-pentanol, benzyl alcohol, an isomer thereof, or a combination
thereof.
54. The topical composition of claim 51, wherein the composition
comprises stabilized hydrogen peroxide in an amount of about 40%
w/w of the composition.
55. The topical composition of claim 51, wherein the composition
comprises stabilized hydrogen peroxide in an amount of about 45%
w/w of the composition.
56. The topical composition of claim 51, wherein the stabilized
hydrogen peroxide comprises a stabilizer selected from the group
consisting of stannate, sodium pyrophosphate, organophosphonate,
nitrate, phosphoric acid, colloidal silicate, or a combination
thereof.
57. The topical composition of claim 51, further comprising a
gelling agent.
58. The topical composition of claim 57, wherein the gelling agent
is selected from polycarbophil, polyvinyl pyrrolidone, poloxamer,
bentonite, high molecular weight cross linked copolymers of acrylic
acid and a hydrophobic comonomer or a copolymer, silicates,
hyaluronic acids, cross-linked hyaluronic acids, a combination
thereof, or a compositional or chemical equivalent thereof.
59. The topical composition of claim 51, wherein the composition
has a surface tension of about 42 mNm-1 to about 55 mNm-1 at
37.degree. C.
60. The topical composition of claim 51, wherein the alcohol is in
an amount sufficient to decrease a surface tension of the
composition to a level that effectively increases the penetration
of the composition into crevices, invaginations and/or surface
irregularities of a skin lesion.
61. The topical composition of claim 51, wherein the alcohol is in
an amount sufficient to decrease surface tension while minimizing
spread of the composition onto non-targeted skin when applied to a
targeted lesion.
62. The topical composition of claim 51, wherein the composition is
stable for at least two years at 5.degree. C., at least one year at
30.degree. C., at least 6 months at 40.degree. C., or a combination
thereof.
63. The topical composition of claim 51, wherein the topical
composition comprises about 45% w/w stabilized cosmetic-grade
hydrogen peroxide and about 5% w/w alcohol, and wherein the topical
composition has a surface tension of about 42 mNm-1 to about 55
mNm-1 at 37.degree. C.
64. The topical composition of claim 51, wherein the topical
composition comprises about 40% w/w stabilized cosmetic-grade
hydrogen peroxide and about 5% w/w alcohol, and wherein the topical
composition has a surface tension of about 42 mNm-1 to about 55
mNm-1 at 37.degree. C.
65. The topical composition of claim 51, wherein the topical
composition comprises about 40% w/w stabilized hydrogen peroxide
and about 5% w/w alcohol.
66. The topical composition of claim 51, wherein the topical
composition comprises about 45% w/w stabilized hydrogen peroxide
and about 5% w/w alcohol.
67. The topical composition of claim 51, wherein the topical
composition has a mean steady state release of hydrogen peroxide
between 0.5 hours and 4 hours of between about 1000
.mu.g/cm.sup.2/hour and about 1750 .mu.g/cm.sup.2/hour.
68. The topical composition of claim 51, wherein the topical
composition has a mean redox potential of about 415 mV to about 430
mV.
69. The topical composition of claim 51, wherein the topical
composition has a pH of about 1.7 to about 3.7.
70. A topical composition comprising about 25% w/w to about 70% w/w
stabilized hydrogen peroxide and a surface tension modifying
agent.
71. The topical composition of claim 70, wherein the composition
comprises stabilized hydrogen peroxide in an amount of about 32.5%
w/w to about 50% w/w.
72. The topical composition of claim 70, wherein the stabilized
hydrogen peroxide comprises a stabilizer selected from the group
consisting of stannate, sodium pyrophosphate, organophosphonate,
nitrate, phosphoric acid, colloidal silicate, or a combination
thereof.
73. The topical composition of claim 70, wherein the surface
tension modifying agent is selected from an alcohol, ethanol,
butanol, PEG (polyethylene glycol) stearate, polysorbate, or a
combination thereof.
74. The topical composition of claim 73, wherein the alcohol is a
primary alcohol, a secondary alcohol, a tertiary alcohol, or a
combination thereof.
75. The topical composition of claim 73, wherein the alcohol is
selected from methanol, ethanol, butanol, 1-propanol, pentanol,
hexanol, octanol, nonanol, decanol, 2-butanol, 2-propanol,
2-pentanol, benzyl alcohol, an isomer thereof, or a combination
thereof.
76. The topical composition of claim 73, wherein the alcohol is
2-propanol.
77. The topical composition of claim 70, wherein the surface
tension modifying agent is in an amount sufficient to decrease a
surface tension of the composition to a level that effectively
increases the penetration of the composition into crevices,
invaginations and/or surface irregularities of a skin lesion.
78. The topical composition of claim 70, wherein the surface
tension modifying agent is in an amount sufficient to decrease
surface tension while minimizing spread of the composition onto
non-targeted skin when applied to a targeted lesion.
79. The topical composition of claim 70, wherein the surface
tension modifying agent is in an amount of about 0.5% w/w to about
25% w/w.
80. The topical composition of claim 70, wherein the topical
composition comprises about 40% w/w stabilized hydrogen peroxide
and about 0.5% w/w to about 25% w/w surface tension modifying
agent.
81. The topical composition of claim 70, wherein the topical
composition comprises about 45% w/w stabilized hydrogen peroxide
and about 0.5% w/w to about 25% w/w surface tension modifying
agent.
82. The topical composition of claim 70, wherein the composition
has a surface tension of about 42 mNm-1 to about 55 mNm-1 at
37.degree. C.
83. The topical composition of claim 70, wherein the composition is
stable for at least two years at 5.degree. C., at least one year at
30.degree. C., at least 6 months at 40.degree. C., or a combination
thereof.
84. The topical composition of claim 70, wherein the topical
composition has a mean steady state release of hydrogen peroxide
between 0.5 hours and 4 hours of between about 1000
.mu.g/cm.sup.2/hour and about 1750 .mu.g/cm.sup.2/hour.
85. The topical composition of claim 70, wherein the topical
composition has a mean redox potential of about 415 mV to about 430
mV.
86. The topical composition of claim 70, wherein the topical
composition has a pH of about 1.7 to about 3.7.
Description
BRIEF SUMMARY
[0001] Embodiments in this disclosure are directed to a composition
comprising hydrogen peroxide and an alcohol. In some embodiments,
the hydrogen peroxide is stabilized hydrogen peroxide. In some
embodiments, the hydrogen peroxide may be a standard grade, food
grade, chemical synthesis grade, semiconductor grade, high-test
hydrogen peroxide grade, antimicrobial grade, drinking water grade,
pharmaceutical grade or cosmetic grade hydrogen peroxide. In some
embodiments, the alcohol may be selected from a primary alcohol, a
secondary alcohol, a tertiary alcohol, or a combination thereof. In
some embodiments, the alcohol may be selected from 2-propanol,
methanol, butanol, 1-propanol, pentanol, hexanol, octanol, nonanol,
decanol, 2-pentanol, 2-butanol, benzyl alcohol, ethanol, an isomer
thereof, or a combination thereof. In some embodiments, the
hydrogen peroxide is in an amount up to about 50% of the
composition. In some embodiments the alcohol is in a quantity
sufficient to decrease the surface tension of the composition. In
some embodiments, the alcohol is in an amount up to about 5% of the
composition. In some embodiments, the composition is a solution. In
some embodiments, the composition is a gel formulation. In some
embodiments, the composition comprises two or more separate
components that may be admixed before, at, or near the time of
use.
[0002] Some embodiments are directed to a topical composition
comprising up to about 50% hydrogen peroxide and up to 5%
2-propanol. In some embodiments, the hydrogen peroxide is a
stabilized hydrogen peroxide. In some embodiments, the topical
composition further includes a stabilizer. The stabilizer may be
selected from stannate, sodium pyrophosphate, organophosphonate,
nitrate, phosphoric acid, colloidal silicate, any stabilizer known
in the art, or a combination thereof. In some embodiments, the
2-propanol is in an amount sufficient to decrease the surface
tension while minimizing spread of the composition onto
non-targeted skin when applied to a targeted lesion. The
composition may be stable for at least two years at 5.degree. C.,
at least one year at 30.degree. C., at least 6 months at 40.degree.
C., or a combination thereof.
[0003] In some embodiments, the topical composition comprises about
45% stabilized cosmetic-grade hydrogen peroxide and about 5%
2-propanol, and wherein the topical composition has a surface
tension of about 42 mNm-1 to about 55 mNm-1 at 37.degree. C. In
some embodiments, the topical composition comprises about 40%
stabilized cosmetic-grade hydrogen peroxide and about 5%
2-propanol, and wherein the topical composition has a surface
tension of about 42 mNm-1 to about 55 mNm-1 at 37.degree. C. In
some embodiments, the topical composition comprises about 32.5%
stabilized cosmetic-grade hydrogen peroxide and about 5%
2-propanol, and wherein the topical composition has a surface
tension of about 42 mNm-1 to about 55 mNm-1 at 37.degree. C. In
some embodiments, the topical composition comprises about 25%
stabilized cosmetic-grade hydrogen peroxide and about 5%
2-propanol, and wherein the topical composition has a surface
tension of about 42 mNm-1 to about 55 mNm-1 at 37.degree. C.
[0004] Some embodiments are directed to a composition comprising
hydrogen peroxide and a surface tension modifying agent. In some
embodiments, the surface tension modifying agent is an agent stable
in compositions comprising concentrations of hydrogen peroxide
disclosed in embodiments herein. In some embodiments, the surface
tension modifying agent is in a quantity sufficient to enhance the
therapeutic efficacy of the composition. In some embodiments, the
surface tension modifying agent is in a quantity sufficient to
modify the surface tension while maintaining stability of the
composition sufficient for use as a commercially viable
formulation. In some embodiments, the surface tension modifying
agent is an alcohol. In some embodiments, the surface tension
modifying agent is 2-propanol.
[0005] Embodiments herein also describe a method of treating a skin
condition comprising administering a composition having up to about
50% hydrogen peroxide and an alcohol to a subject in need thereof.
The skin condition may be a virally induced or non-virally induced
cutaneous growth or proliferation. The skin condition may be a
benign neoplasm, premalignancy or malignancy. The skin condition
may be an inflammatory condition. The skin condition may be a
hyperproliferative condition. The skin condition may be aging
including intrinsic (e.g., chronological) and extrinsic changes
(e.g., photoaging, ultraviolet light induced changes), pigmentary
changes, fine lines and rhytides. In some embodiments, the skin
condition may be selected from Human Papilloma Virus induced
lesions e.g., warts, common warts, palmoplantar warts, flat warts,
recurrent warts, recalcitrant warts, treatment naive warts,
epidermodysplasia verruciformis related warts, anogenital warts,
condyloma accuminatum, cervical dysplasias or neoplasias, e.g.,
cervical intraepithelial neoplasia (CIN); Herpesvirus related
lesions including those induced by HHV-1 (HSV-1), HHV-2 (HSV-2),
HHV-3 (varicella-zoster virus) e.g., chicken pox, Herpes zoster,
shingles; Poxvirus induced lesions e.g., molluscum contagiosum,
orf; callus, cutaneous horns, corns, acrochordons, fibroepithelial
polyps, prurigo nodularis, actinic keratoses, squamous cell
carcinoma, squamous cell carcinoma in situ, keratoacanthoma, basal
cell carcinoma, cutaneous lymphomas and benign lymphocytic
infiltrates & hyperplasias of the skin, clear cell acanthoma,
large cell acanthoma, epidermolytic acanthoma, porokeratosis,
hyperkeratosis, keratosis pilaris lichenoid keratosis, acanthosis,
acanthosis nigricans, confluent and reticulated papillomatosis,
nevi, including e.g., dermal nevi, epidermal nevi, compound nevi,
ILVEN (inflammatory linear verrucous epidermal nevi), nevus
sebaceous, nevus comedonicus, and the like; acne, e.g., comedonal
acne, inflammatory acne, papular acne, pustular acne, cystic acne;
cysts, e.g., epidermoid cysts, milia, trichilemmal cysts,
follicular cysts, proliferating cysts, dermoid cysts, pilonidal
cysts, apocrine cysts, eccrine cysts, sebaceous cysts, mucous
cysts, myxoid cysts, ganglion cysts, synovial cysts, vellus hair
cysts, steatocystoma, hidrocystoma; adnexal neoplasms e.g.,
trichofolliculoma, fibrofolliculoma, perifollicular fibroma,
trichodiscoma, nevus sebaceous, chondroid syringoma,
trichoepithelioma, trichoblastoma, desmoplastic trichoepithelioma,
pilomatricoma, pilomatrical carcinoma, tricholemmoma, trichelemmal
carcinoma, tumor of the follicular infundibulum, tricoadenoma,
proliferating pilar tumor, sebaceous hyperplasia, sebaceous
adenoma, sebaceous epithelioma, sebaceous carcinoma, syringoma,
poroma, hidradenoma, apocrine hidradenoma, spiradenoma, cylindroma,
eccrine nevus (eccrine hamartoma), papillary adenoma, papillary
adenocarcinoma; benign melanocytic proliferations or neoplasms
e.g., ephilides, cafe-au-lait macules, Becker's melanosis,
lentigines, solar lentigines, lentigo simplex, mucosal melanocytic
lesions, Mongolian spots, Nevus of Ota, blue nevus, common acquired
melanocytic nevi (nevocellular nevus, "moles"), congenital nevi,
nevus spilus, recurrent nevi; vascular and perivascular neoplasms
and reactive hyperplasias e.g., hemangiomas, cherry angiomas,
hobnail hemangiomas (targeted hemosiderotic hemangiomas), tufted
angiomas, hemangioendotheliomas, angiolymphoid hyperplasia with
eosinophilia (ALHE), Glomus tumors (glomangiomas),
hemangiopericytomas; cutaneous neural and neuroendocrine neoplasms
e.g., neuromas, Schwannomas, neurofibromas, nerve sheath tumor,
nerve sheath myxoma, neurothekeoma, granular cell tumor; fibrotic
and fibrohistiocytic proliferations e.g., acrochordons,
fibroepithelial polyps, fibromas, fibrous papules, angiofibromas,
pearly penile papules, periungual fibromas, dermatofibromas,
fibrokeratomas, sclerotic or pleomorphic fibromas, connective
tissue nevi; cutaneous scars, hyperplasias, keloids, rosacea,
cutaneous fungal, dermatophyte & mold infections,
onychomycosis, hyperpigmentation, rhytides, psoriasis, malignant
melanoma, seborrheic keratosis, seborrheic keratosis variants
including e.g., dermatosis papulosis nigra, inverted follicular
keratosis/keratoma warty dyskeratosis/warty dyskeratoma,
acrokeratosis verruciformis, stucco keratosis; or a combination
thereof.
[0006] Some embodiments describe a method of treating warts
comprising administering a composition having up to about 50%
hydrogen peroxide and an alcohol to a subject in need thereof.
[0007] Some embodiments describe a method of treating seborrheic
keratosis comprising administering a composition having up to about
50% hydrogen peroxide and an alcohol to a subject in need thereof.
In some embodiments, the alcohol is in an amount capable of
decreasing the surface tension of the composition. In some
embodiments, the alcohol is in an amount capable of increasing the
wettability of the surface of the skin or skin lesion. In some
embodiments, the alcohol is in an amount capable of increasing the
permeability of the composition into the subject's skin and/or the
skin lesion. In some embodiments, the alcohol is in an amount
capable of enhancing the clinical efficacy of the composition. In
some embodiments, the alcohol is in an amount capable of enhancing
the clinical efficacy of the composition while maintaining
stability sufficient for a commercially viable composition.
[0008] Some embodiments herein are directed to a topical solution
formulation comprising up to about 50% hydrogen peroxide and an
alcohol. In some embodiments, the solution is comprised of two or
more parts to be mixed at or immediately before the time of
application.
[0009] Some embodiments herein are directed to a gel composition
comprising up to about 50% hydrogen peroxide, an alcohol, and a
gelling agent. In some embodiments, the gel composition is
comprised of two or more parts that may be mixed at or immediately
before the time of application.
[0010] Some embodiments herein describe a composition consisting
essentially of up to about 50% hydrogen peroxide and an alcohol.
Some embodiments herein describe a composition consisting of up to
about 50% hydrogen peroxide and an alcohol. In some embodiments,
the alcohol is a primary alcohol, a secondary alcohol, a tertiary
alcohol, or a combination thereof. In some embodiments, the alcohol
is not 1-propanol, ethanol, butanol, pentanol, hexanol, octanol,
nonanol, decanol, 2-butanol, 2-pentanol, or benzyl alcohol. In some
embodiments, the alcohol is 2-propanol.
[0011] Some embodiments herein are directed toward devices for
administering the compositions of embodiments herein. In some
embodiments, the devices may include an applicator configured to
safely and effectively deliver the compositions of embodiments
herein to the targeted skin of a patient. Some embodiments herein
include an applicator configured to store and dispense a topical
composition comprising an agent selected from a caustic agent, an
unstable agent or a combination thereof, the applicator comprising
a frangible ampoule having the agent disposed therein, an
applicator body having the frangible ampoule arranged therein; an
applicator hub in fluid communication with the applicator body; a
tip arranged at a proximal end of the applicator hub; and a filter
arranged between the frangible ampoule and the tip. In some
embodiments, the topical composition comprises from about 25% to
about 50% hydrogen peroxide and up to 5% 2-propanol. In some
embodiments, the agent comprises from about 25% hydrogen peroxide
to about 50% hydrogen peroxide. In some embodiments, the frangible
ampoule further includes up to 5% 2-propanol. In some embodiments,
the applicator body further comprises an additional ingredient of
the topical composition disposed therein, whereby the agent is
released from the frangible ampoule responsive to the frangible
ampoule being ruptured and is mixed with the additional ingredient
in the applicator body prior to administration of the topical
composition. In some embodiments, the topical composition is
released from the frangible ampoule responsive to the frangible
ampoule being ruptured and flows through the applicator body, the
filter, and out of the applicator through the tip. In some
embodiments, the applicator further includes a pressure area
arranged on an outer surface of the applicator body to indicate a
portion of the applicator body to apply pressure to rupture the
frangible ampoule.
[0012] Some embodiments are directed to an applicator configured to
store and dispense a topical composition comprising from about 25%
to about 50% hydrogen peroxide and up to 5% 2-propanol, the
applicator comprising a frangible ampoule having the topical
composition disposed therein, an applicator body having the
frangible ampoule arranged therein, an applicator hub in fluid
communication with the applicator body, a tip arranged at a
proximal end of the applicator body; and a filter arranged between
the frangible ampoule and the tip. In some embodiments, the
frangible ampoule is formed from at least one of glass, plastic,
borosilicate glass, Type 1 borosilicate glass, and tinted glass. In
some embodiments, the applicator body is formed from polypropylene,
high-density polyethylene, low-density polyethylene, polyvinyl
chloride, polyethylene, or a combination thereof. In some
embodiments, the filter is configured to prevent shards of a
ruptured frangible ampoule from passing through and to allow the
topical composition to flow through. In some embodiments, the
filter is formed from at least one of polypropylene, high-density
polyethylene, low-density polyethylene, polyethylene, polystyrene,
a ceramic material, a foam material, sand, diatomaceous earth, and
paper fibers.
[0013] Some embodiments are directed to a method of treating a skin
condition, the method comprising administering a topical
composition comprising up to 50% hydrogen peroxide and up to 5%
2-propanol using an applicator comprising a frangible ampoule
having the topical composition disposed therein, an applicator body
having the frangible ampoule arranged therein, an applicator hub in
fluid communication with the applicator body, a tip arranged at a
proximal end of the applicator hub, and a filter arranged between
the frangible ampoule and the tip. In some embodiments,
administering the topical composition comprises applying a
squeezing force to the exterior surface of the applicator body to
dispense the composition. In some embodiments, administering the
topical composition comprises contacting the tip with a targeted
lesion of the skin condition whereby the topical composition
dispenses through the tip onto the targeted lesion. In some
embodiments, administering the topical composition further
comprises applying pressure to a pressure area arranged on an outer
surface of the applicator body causing the frangible ampoule to
rupture. In some embodiments, administering the topical composition
comprises causing the frangible ampoule to rupture and release the
topical composition through the tip; and contacting the tip to a
targeted lesion of the skin condition.
[0014] In some embodiments, the applicator may include a frangible
ampoule configured to store the compositions of embodiments herein
arranged within an applicator body. In some embodiments, the
ampoule may be formed from glass or other similar frangible
materials, such as borosilicate glass. In some embodiments, the
applicator body may be formed from various flexible materials,
including, without limitation high-density polyethylene (HDPE),
low-density polyethylene (LDPE) or various combinations or blends
thereof. In some embodiments, the compositions of embodiments
herein may be released from the ampoule by applying manual pressure
(for instance, "squeezing") on the applicator body in a direction
toward the ampoule sufficient to cause the ampoule to break apart.
In some embodiments, the compositions of embodiments herein
released from the ampoule may flow through a filter configured to
filter glass shards from the broken ampoule while allowing the
compositions of embodiments herein to flow therethrough. In some
embodiments, at least one portion of the applicator may include a
hydrophobic material, such as the filter and/or the tip. In some
embodiments the hydrophobic material is composed of polyester or
co-polyester polymers, acrylic, modified acrylic (e.g.,
modacrylic), polypropylene, polyethylene or combinations or
mixtures thereof. Non-limiting examples of hydrophobic materials
may also include materials including, coated with, and/or modified
by silanes, alkylsilanes, fluoroalkylsilanes, silicone,
combinations thereof, and derivatives thereof. In some embodiments,
the hydrophobic portions of the applicator may operate to impede,
reduce, restrict, prevent, and/or substantially prevent the
compositions of embodiments herein that have been released from the
ampoule from flowing through portions of the applicator and/or out
of the tip of the applicator. In some embodiments, the compositions
of embodiments herein may flow through the filter and out of the
applicator via an applicator tip for application on the skin of a
patient. In some embodiments, the tip may include a flocked portion
formed from filaments of various chemically compatible and
non-reactive materials, such as nylon.
DESCRIPTION OF THE FIGURES
[0015] FIG. 1 illustrates the mean cumulative amount of hydrogen
peroxide released per unit area across silicone membrane
(.mu.g/cm.sup.2) following application of all 40% w/w hydrogen
peroxide formulations. Each time point represents the mean.+-.SD
(n=5-6).
[0016] FIG. 2 illustrates the mean cumulative amount of hydrogen
peroxide released per unit area across silicone membrane
(.mu.g/cm.sup.2) following application of 40% w/w hydrogen peroxide
formulations containing 1-propanol. Each time point represents the
mean.+-.SD (n=5-6).
[0017] FIG. 3 illustrates the mean cumulative amount of hydrogen
peroxide released per unit area across silicone membrane
(m/cm.sup.2) following application of 40% w/w hydrogen peroxide
formulations containing 2-propanol. Each time point represents the
mean.+-.SD (n=5-6).
[0018] FIG. 4 illustrates the steady state release of hydrogen
peroxide, calculated between 0.5 and 4 h (.mu.g/cm.sup.2/h)
following application of hydrogen peroxide formulations at varying
levels of propanol. Each data point represents the mean.+-.SD,
n=5-6.
[0019] FIG. 5 illustrates the difference in the steady state
release of hydrogen peroxide (Flux [1-propanol]-Flux [2-propanol])
for 5, 10, 15 and 20% w/w (1-propanol and 2-propanol).
[0020] FIG. 6 illustrates the mean surface tension (mN/m) of the
different hydrogen peroxide formulations assessed containing either
1- or 2-propanol.
[0021] FIG. 7 illustrates the grades and descriptors for the Wart
Improvement Assessment score and the Wart Severity Assessment
score.
[0022] FIG. 8 illustrates the mean Wart Improvement Assessment
score by visit.
[0023] FIG. 9 illustrates the mean change in baseline in the Wart
Severity Assessment score by visit.
[0024] FIG. 10 illustrates the redox potential (mV) of all 40% w/w
hydrogen peroxide formulations containing 1- and 2-propanol, with
and without skin at t=0, 1, 6 and 24 h. Each time point represents
the mean.+-.range, n=3.
[0025] FIG. 11 illustrates the redox potential (mV) of 40% w/w
hydrogen peroxide formulations containing 5% w/w 1- or 2-propanol,
in with and without skin at t=0, 1, 6 and 24 h. Each time point
represents the mean.+-.range, n=3.
[0026] FIG. 12 depicts an illustrative applicator according to a
first embodiment.
[0027] FIGS. 13A-13C depicts an illustrative applicator according
to a second embodiment.
[0028] FIGS. 14A and 14B depict multiple views of an illustrative
applicator body according to some embodiments.
[0029] FIG. 15 depicts an illustrative end cap of an applicator
according to some embodiments.
[0030] FIG. 16 depicts an illustrative holed flocked tip (or
"applicator hub") according to some embodiments.
[0031] FIGS. 17A and 17B depict an illustrative protective cap
according to a first embodiment.
[0032] FIGS. 18A and 18B depict an illustrative protective cap
according to a second embodiment.
DETAILED DESCRIPTION
[0033] Before the present compositions and methods are described,
it is to be understood that this invention is not limited to the
particular processes, compositions, or methodologies described, as
these may vary. It is also to be understood that the terminology
used in the description is for the purpose of describing the
particular versions or embodiments only, and is not intended to
limit the scope of the present invention which will be limited only
by the appended claims. Unless defined otherwise, all technical and
scientific terms used herein have the same meanings as commonly
understood by one of ordinary skill in the art. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of embodiments of the
present invention, the preferred methods, devices, and materials
are now described. All publications mentioned herein are
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0034] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "skin lesion" is a reference to
one or more skin lesions and equivalents thereof known to those
skilled in the art, and so forth.
[0035] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0036] "Administering", when used in conjunction with a
therapeutic, means to administer a therapeutic directly into or
onto a target tissue or to administer a therapeutic to a subject,
whereby the therapeutic positively impacts the tissue to which it
is targeted. Thus, as used herein, the term "administering", when
used in conjunction with a therapeutic, can include, but is not
limited to, providing a therapeutic to a subject systemically by,
for example, intravenous injection, whereby the therapeutic reaches
the target tissue. Administering a composition or therapeutic may
be accomplished by, for example, injection, oral administration,
topical administration, or by these methods in combination with
other known techniques. Such combination techniques may include
heating, radiation, ultrasound and the use of delivery agents.
Preferably, administering is a self-administration, wherein the
therapeutic or composition is administered by the subject
themselves. Alternatively, administering may be administration to
the subject by a health care provider.
[0037] "Providing", when used in conjunction with a therapeutic,
means to administer a therapeutic directly into or onto a target
tissue, or to administer a therapeutic to a subject whereby the
therapeutic positively impacts the tissue to which it is
targeted.
[0038] The term "animal" as used herein includes, but is not
limited to, humans and non-human vertebrates such as wild, domestic
and farm animals.
[0039] The term "patient" or "subject" as used herein is an animal,
particularly a human, suffering from an unwanted disease or
condition that may be treated by the therapeutic and/or
compositions described herein.
[0040] The term "improves" is used to convey that the embodiments
provided herein change either the characteristics and/or the
physical attributes of the tissue to which the therapeutic
composition is being provided, applied or administered. The term
"improves" may also be used in conjunction with a diseased state
such that when a diseased state is "improved" the symptoms or
physical characteristics associated with the diseased state are
diminished, reduced or eliminated.
[0041] The term "inhibiting" generally refers to prevention of the
onset of the symptoms, alleviating the symptoms, or eliminating the
disease, condition or disorder.
[0042] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where the event occurs and instances
where it does not.
[0043] As used herein, "room temperature" means an indoor
temperature of from about 20.degree. C. to about 25.degree. C. (68
to 77.degree. F.).
[0044] Throughout the specification of the application, various
terms are used such as "primary," "secondary," "first," "second,"
and the like. These terms are words of convenience in order to
distinguish between different elements, and such terms are not
intended to be limiting as to how the different elements may be
utilized.
[0045] By "pharmaceutically acceptable," "physiologically
tolerable," and grammatical variations thereof, as they refer to
compositions, carriers, diluents, and reagents or other ingredients
of the formulation, can be used interchangeably and represent that
the materials are capable of being administered without the
production of undesirable physiological effects such as rash,
burning, irritation or other deleterious effects to such a degree
as to be intolerable to the recipient thereof.
[0046] As used herein, the term "cosmetically acceptable" and
grammatical variations thereof, as they refer to compositions,
carriers, diluents, and reagents or other ingredients of the
formulation, represent that the materials used and final
composition are not irritating or otherwise harmful to the patient
in general and to the skin, in particular, and preferably are
pleasant and well tolerated with respect to general appearance, pH,
color, smell and texture (feel), that they are not, for example,
unacceptably sticky (tacky), oily or drying, and that they do
spread easily, absorb into the skin at an acceptable rate of
absorption, and are generally moisturizing.
[0047] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent or improve an
unwanted condition or disease of a subject. In part, embodiments
described herein may be directed to the treatment of various skin
diseases, conditions or disorders or symptoms thereof, including,
but not limited to, benign proliferations, neoplasms,
premalignancies or malignancies of the skin. The skin condition may
be a virally induced or non-virally induced cutaneous growth or
proliferation. The skin condition may be an inflammatory condition.
The skin condition may be a hyperproliferative condition. The skin
condition may be ageing including intrinsic and extrinsic changes
(e.g., photoaging (ultraviolet light induced changes)), pigmentary
changes, fine lines and rhytides. In some embodiments, the skin
condition may be selected from Human Papilloma Virus induced
lesions e.g., warts, common warts, palmoplantar warts, flat warts,
recurrent warts, recalcitrant warts, treatment naive warts,
epidermodysplasia verruciformis related warts, anogenital warts,
condyloma accuminatum, cervical dysplasias or neoplasias, e.g.,
cervical intraepithelial neoplasia (CIN); Herpesvirus related
lesions including those induced by HHV-1 (HSV-1), HHV-2 (HSV-2),
HHV-3 (varicella-zoster virus) e.g., chicken pox, Herpes zoster,
shingles; Poxvirus induced lesions e.g., molluscum contagiosum,
orf; callus, cutaneous horns, corns, acrochordons, fibroepithelial
polyps, prurigo nodularis, actinic keratoses, squamous cell
carcinoma, squamous cell carcinoma in situ, keratoacanthoma, basal
cell carcinoma, cutaneous lymphomas and benign lymphocytic
infiltrates & hyperplasias of the skin, clear cell acanthoma,
large cell acanthoma, epidermolytic acanthoma, porokeratosis,
hyperkeratosis, keratosis pilaris, lichenoid keratosis, acanthosis,
acanthosis nigricans, confluent and reticulated papillomatosis,
nevi, including e.g., dermal nevi, epidermal nevi, compound nevi,
ILVEN (inflammatory linear verrucous epidermal nevi), nevus
sebaceous, nevus comedonicus, and the like; acne, e.g., comedonal
acne, inflammatory acne, papular acne, pustular acne, cystic acne;
cysts, e.g., epidermoid cysts, milia, trichilemmal cysts,
follicular cysts, proliferating cysts, dermoid cysts, pilonidal
cysts, apocrine cysts, eccrine cysts, sebaceous cysts, mucous
cysts, myxoid cysts, ganglion cysts, synovial cysts, vellus hair
cysts, steatocystoma, hidrocystoma; adnexal neoplasms e.g.,
trichofolliculoma, fibrofolliculoma, perifollicular fibroma,
trichodiscoma, nevus sebaceous, chondroid syringoma,
trichoepithelioma, trichoblastoma, desmoplastic trichoepithelioma,
pilomatricoma, pilomatrical carcinoma, tricholemmoma, trichelemmal
carcinoma, tumor of the follicular infundibulum, tricoadenoma,
proliferating pilar tumor, sebaceous hyperplasia, sebaceous
adenoma, sebaceous epithelioma, sebaceous carcinoma, syringoma,
poroma, hidradenoma, apocrine hidradenoma, spiradenoma, cylindroma,
eccrine nevus (eccrine hamartoma), papillary adenoma, papillary
adenocarcinoma; benign melanocytic proliferations or neoplasms
e.g., ephilides, cafe-au-lait macules, Becker's melanosis,
lentigines, solar lentigines, lentigo simplex, mucosal melanocytic
lesions, Mongolian spots, Nevus of Ota, blue nevus, common acquired
melanocytic nevi (nevocellular nevus, "moles"), congenital nevi,
nevus spilus, recurrent nevi; vascular and perivascular neoplasms
and reactive hyperplasias e.g., hemangiomas, cherry angiomas,
hobnail hemangiomas (targeted hemosiderotic hemangiomas), tufted
angiomas, hemangioendotheliomas, angiolymphoid hyperplasia with
eosinophilia (ALHE), Glomus tumors (glomangiomas),
hemangiopericytomas; cutaneous neural and neuroendocrine neoplasms
e.g., neuromas, Schwannomas, neurofibromas, nerve sheath tumor,
nerve sheath myxoma, neurothekeoma, granular cell tumor; fibrotic
and fibrohistiocytic proliferations e.g., acrochordons,
fibroepithelial polyps, fibromas, fibrous papules, angiofibromas,
pearly penile papules, periungual fibromas, dermatofibromas,
fibrokeratomas, sclerotic or pleomorphic fibromas, connective
tissue nevi; cutaneous scars, hyperplasias, keloids, rosacea,
cutaneous fungal, dermatophyte & mold infections,
onychomycosis, hyperpigmentation, rhytides, psoriasis, malignant
melanoma, seborrheic keratosis, seborrheic keratosis variants
including e.g., dermatosis papulosis nigra, inverted follicular
keratosis/keratoma warty dyskeratosis/warty dyskeratoma,
acrokeratosis verruciformis, stucco keratosis; or a combination
thereof.
[0048] As used herein, the term "stabilized hydrogen peroxide"
refers to a hydrogen peroxide comprising a stabilizer or a blend of
stabilizers useful for dilution of the hydrogen peroxide into a
concentration that can be incorporated into a stable commercial
formulation for topical application to skin lesions for the
treatment of skin conditions described herein. In some embodiments,
the hydrogen peroxide may be obtained from a commercial source. The
amount and type of stabilizer(s) used in the hydrogen peroxide
formulation may be proprietary to and/or a trade secret of the
commercial source. In some embodiments, the stabilized hydrogen
peroxide is a hydrogen peroxide of high concentration. Though pure
hydrogen peroxides of high concentration are typically stable,
stabilizers may be used in hydrogen peroxide formulations, usually
when obtained through commercial sources, in order to stabilize
diluted versions of the "high concentration" hydrogen peroxide
formulation. Some hydrogen peroxide formulations have stabilizers
in concentrations (in total and/or individually) sufficient to
provide stabilization of diluted hydrogen peroxide for particular
uses or in particular industries. In some embodiments, the
stabilized hydrogen peroxide has been approved by the Food and Drug
Administration (FDA) for topical administration to humans. In some
embodiments, the stabilized hydrogen peroxide has a drug master
file at the FDA and been approved by the FDA for topical
administration to humans.
[0049] As used herein, the term "clinical efficacy" refers to the
ability of an ingredient or composition to produce a desired
effect. For example, in some embodiments, the desired effect may
include, without limitation, decreasing the surface tension of the
composition, increasing the wettability of the surface of the skin
or skin lesion, increasing the permeability of the composition into
the subject's skin, skin lesion, or surface imperfections,
including crevices, invaginations and irregularities of the skin or
skin lesion, decreasing the size of the target lesion, improving
the shape and/or appearance of the target lesion, improving the
target lesion or treated area and/or removing the target lesion, or
a combination thereof.
[0050] The terms "therapeutically effective" or "effective", as
used herein, may be used interchangeably and refer to an amount of
a therapeutic composition of embodiments described herein. For
example, a therapeutically effective amount of a composition is an
amount of the composition, and particularly the active ingredient,
such as hydrogen peroxide, that generally achieves the desired
effect.
[0051] A "therapeutically effective amount" or "effective amount"
of a composition is an amount necessary or sufficient to achieve
the desired result. The activity contemplated by the embodiments
herein includes medically therapeutic, cosmetically therapeutic
and/or prophylactic treatment, as appropriate. The specific dose of
a compound administered according to embodiments of the present
invention to obtain therapeutic and/or prophylactic effects will,
of course, be determined by the particular circumstances
surrounding the case, including, for example, the compound
administered, the route of administration, and the condition being
treated. However, the effective amount administered can be
determined by the practitioner or manufacturer or patient in light
of the relevant circumstances including the condition to be
treated, the choice of compound to be administered, and the chosen
route of administration, and therefore, the above dosage ranges are
not intended to limit the scope of the invention in any way. A
therapeutically effective amount of the compound of embodiments
herein is typically an amount such that when it is administered in
a physiologically tolerable excipient composition, it is sufficient
to achieve an effective systemic concentration or local
concentration in or on the tissue to achieve the desired
therapeutic or clinical outcome.
[0052] The terms "treat," "treated," or "treating" as used herein
refers to therapeutic treatment, cosmetic treatment and/or
prophylactic or preventative measures, wherein the object is to
prevent or slow down (lessen) an undesired physiological condition,
disorder or disease, or to obtain beneficial or desired clinical
results. For the purposes of this disclosure, beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms; diminishment of the extent of the condition, disorder or
disease; stabilization (i.e., not worsening) of the state of the
condition, disorder or disease; delay in onset or slowing of the
progression of the condition, disorder or disease; amelioration of
the condition, disorder or disease state; and remission (whether
partial or total), whether detectable or undetectable, or
enhancement or improvement of the condition, disorder or disease.
Treatment includes eliciting a clinically significant response
without excessive levels of side effects.
[0053] As used herein, the term "consists of" or "consisting of"
means that the formulation or method includes only the elements,
steps, or ingredients specifically recited in the particular
claimed embodiment or claim.
[0054] As used herein, the term "consisting essentially of" or
"consists essentially of" means that the formulation or method
includes only the specified materials or steps and those that do
not materially affect the basic and novel characteristics of the
claimed invention.
[0055] Generally speaking, the term "tissue" refers to any
aggregation of similarly specialized cells which are united in the
performance of a particular function.
[0056] Seborrheic keratosis (SK) is one of the most common skin
tumors in man. These benign epithelial skin tumors are most
commonly seen in older individuals, increasing in prevalence with
increasing age, and affect men and women roughly equally. The
growths may be solitary or occur in large numbers and typically
present as well demarcated, elevated or "stuck-on" appearing
papules or plaques that may vary in color e.g., from flesh-colored,
to shades of yellow, gray, brown, or black. Though benign, they are
often cosmetically worrisome to patients, must sometimes be
distinguished from other benign or malignant skin tumors, and may
become symptomatic. They may be pruritic, irritated, bleed, and may
be painful when traumatized particularly when located in areas
prone to friction and trauma such as belt-lines and brassiere-strap
lines.
[0057] Patients may seek treatment of SK for cosmetic reasons,
especially if they are large, pigmented, and/or if multiple lesions
are present, or simply because the lesions are commonly associated
with advancing age. Removal may be medically indicated, however,
for lesions that become irritated, pruritic, inflamed, or painful,
or for lesions that the clinician feels require histologic
confirmation of the diagnosis.
[0058] Numerous surgical treatment options for SK exist, and
include a plethora of destructive/ablative modalities such as,
e.g., liquid nitrogen cryotherapy, electrodesiccation, lasers of
various wavelengths (ablative and non-ablative), radio-frequency
ablation, dermabrasion, and surgical removal by curettage or
surgical excision. There is, however, a notable lack of
well-controlled clinical trials comparing the efficacy,
complications and complication rates of these treatments. There is
great variability among practitioners in the methods employed using
each of these techniques (e.g., variability in contact time and
method of freezing the lesions with liquid nitrogen) with great
variability of the results. None of these treatments is, in fact,
approved by the Food and Drug Administration (FDA) for the
treatment of seborrheic keratosis. While these methods can achieve
cure rates, many require specialized training and the use of
expensive equipment, they are painful and may require anesthesia
and/or analgesia, and they are often complicated by significant
adverse cosmetic outcomes. Both hypopigmentation and
hyperpigmentation, which may be transient, but often permanent, are
common, as is scarring at the treatment site, and the typical
post-surgical risks of bleeding and infection increase the risk
that the result of the treatment of these lesions may be worse than
the disease itself.
[0059] Numerous topical medical treatments for SK have been
attempted, however no topical therapy has been found to be
consistently effective. For example, ammonium lactate has been
found to be ineffective. Other examples include calcipotriene
ointment, tazarotene cream, imiquimod cream, and Vanicream.RTM.
applied once daily for 16 weeks, all of which have been found to be
ineffective. A single report of the off-label use of tazarotene
0.1% applied twice daily, reported efficacy in only 7/15 (47%) of
subjects, and therapy was complicated by "burning, pruritus and
redness". A report of the use of a topical vitamin D.sub.3 ointment
used once or twice daily for an average of 7.3 months (range 3-12
months) resulted in an 80% or more improvement in lesions in only
30% of patients. Thus there exists in the art a need for a safe and
efficacious topical treatment for seborrheic keratosis.
[0060] Verrucae (Warts) are virally induced lesions caused by
subtypes of the Cutaneous Human Papilloma Virus (HPV) family. HPV
types are a subset of the large group of the DNA papillomavirus
family that are capable of infecting humans and causing cutaneous
lesions. HPV's are ubiquitous in the environment and infection
occurs most commonly as a result of direct contact with individuals
who harbor the virus either clinically (evidence lesions) or
subclinically, indirectly through exposure to contaminated
surfaces, or by autoinoculation of virus from individual lesions to
adjacent uninfected skin. Cutaneous manifestations of HPV infection
include common warts (verruca vulgaris), palmar and plantar warts,
mosaic warts, flat warts, butcher's warts, and others. Subtypes of
the HPV family are also etiologic of oropharyngeal, anogenital,
laryngeal warts, papillomas, dysplasias (e.g., CIN (cervical
intraepithelial neoplasia) carcinoma in situ, carcinomas, and in
the skin lesions seen in epidermodysplasia verruciformis. Common
warts are typically hyperkeratotic, exophytic dome-shaped papules
or nodules (typically associated with HPV types 1, 2 or 4) and are
most commonly located on the fingers (including periungual and
subungual regions), dorsal surfaces of the hands, sites prone to
trauma (e.g., knees, elbows), but may occur at virtually any other
anatomical location. In some embodiments, the skin condition may be
a benign neoplasm, premalignancy or malignancy. The skin condition
may be an inflammatory condition. The skin condition may be a
hyperproliferative condition. The skin condition may be ageing
including intrinsic and extrinsic changes (e.g., photoaging
(ultraviolet light induced changes)), pigmentary changes, fine
lines and rhytides.
[0061] Condyloma acuminata, more commonly known as genital warts,
are typically related to HPV types 6 and 11, 16, 18, and numerous
other subtypes (e.g., 33, 35, 39, 40, 43, 45, 51-56, 58 and
others), and multiple subtypes may exist in a single lesion.
Condyloma acuminata typically present as solitary to multiple
fleshy, soft, verrucoid papules that may be dome-shaped, filiform,
fungating, "cauliflower-like", or form confluent plaques. They are
typically located in the anogenital region (e.g., penis, vulva,
vagina, cervix, perineum, and perianal regions), and may appear in
the oropharynx, larynx and even tracheal mucosa, and rarely other
cutaneous locations (e.g., trunk, extremities). The lesions are
typically benign, but certain HPV subtypes are associated with a
risk of malignant potential (e.g., HPV subtypes 16, 18) and may
lead to cutaneous carcinomas or carcinomas-in-situ such as bowenoid
papulosis or Buschke-Lowenstein tumor, and cervical dysplasias or
neoplasia, e.g., cervical intraepithelial neoplasia (CIN).
[0062] In immunocompetent individuals, many common cutaneous
lesions associated with HPV infection (e.g., warts and condylomata)
spontaneously resolve in less than two years. However, warts can be
large and/or cosmetically unsightly (e.g., face, hands), spread to
distant anatomical regions by autoinoculation, painful (e.g.,
traumatized or on soles of feet), and untreated warts provide a
significant reservoir of HPV infection in the community.
[0063] There are currently no specific antiviral therapies
available to treat cutaneous HPV infection. Existing therapies are
thus directed towards either the direct physical destruction of the
lesions with locally destructive modalities such as cryotherapy,
electrosurgery, curettage, laser therapy, application of acids
(e.g., salicylic acid, trichloroacetic acid); locally cytotoxic
therapies, such as topical podophyllin, cantharidin, or topical or
intralesional 5-fluorouracil, or bleomycin; topical
immunomodulatory therapy (e.g., topical imiquimod, intralesional
candida antigen, topical squaric acid dibutyl ester, oral
cimetidine) or surgical lesion removal. Various of these therapies
are also available as over-the-counter (OTC) wart therapies in
lower concentrations (e.g., topical salicylic acid preparations;
home "freezing" kits). While these methods can achieve cure rates
in some cases, many require multiple visits to a physician's
office, specialized training and the use of expensive equipment;
they are painful and may require anesthesia and/or analgesia, and
they can be complicated by adverse cosmetic outcomes including
scarring at the treatment site, and the typical post-surgical risks
of bleeding and infection. No one therapy is consistently effective
in all cases and in fact, there is great variability among
practitioners in the methods employed using each of these
techniques with great variability of the results. Recurrences are
common and the use of multiple treatment modalities in combination
is often necessary to achieve significant improvement. Thus, there
exists a great unmet need in the art for a safe and efficacious
topical treatment for the cutaneous lesions associated with HPV
infection e.g., warts and condyloma.
[0064] Mollusca are virally induced lesions caused by subtypes of
the DNA poxvirus family of molluscum contagiosum viruses (MCV).
There are four subtypes of MCV, (MCV-1 to 4), with MCV-1 being the
most prevalent and MCV-2 being most common in adults. Like HPV's,
MCV's are ubiquitous in the environment and infection occurs most
commonly as a result of direct contact with individuals who harbor
the virus either clinically (evidence lesions) or subclinically,
indirectly through exposure to contaminated surfaces, or by
autoinoculation of virus from individual lesions to adjacent
uninfected skin. The infection is most common in the pediatric
population, sexually active adults, and the immunocompromised.
Molluscum contagiosum lesions are typically flesh-colored,
dome-shaped umbilicated ("dimpled") papules that may occur singly
or in clusters and are typically located on the trunk groin or
extremities, though may occur on any area of the skin. Individual
lesions may spontaneously resolve in several weeks to several
months, however, the natural history of the infection from
appearance of the first lesions to resolution of the last lesion
may last from six months to five years or more.
[0065] There are currently no U.S. Food and Drug Administration
approved treatments for molluscum contagiosum. There are currently
no specific antiviral therapies available to treat cutaneous MCV
infection. Existing therapies are thus directed towards either the
direct physical destruction of the lesions with locally destructive
modalities such as cryotherapy, electrosurgery, curettage, laser
therapy, unroofing the lesion with e.g., a needle
("needle-pricking"), application of acids or caustics (e.g.,
salicylic acid, potassium hydroxide); locally cytotoxic therapies,
such as topical podophyllin, cantharidin; topical immunomodulatory
therapy (e.g., topical imiquimod, intralesional candida antigen,
nitric acid, oral cimetidine) or surgical lesion removal. While
these methods can achieve cure rates in some cases, many require
multiple visits to a physician's office, specialized training and
the use of expensive equipment; they may be painful and may require
anesthesia and/or analgesia, and may be anxiety producing and
psychologically traumatic, particularly in the pediatric age group.
These treatments may be complicated by adverse cosmetic outcomes
including pigmentary changes (both hyperpigmentation and
hypopigmentation), scarring at the treatment site, bleeding and
infection. No one therapy is consistently effective in all cases
and in fact, there is great variability among practitioners in the
methods employed using each of these techniques with great
variability of the results. The use of multiple treatment
modalities including the treatment of underlying topical conditions
such as atopic dermatitis, which tends to predispose to molluscum
and the spread of the lesions, in combination is often necessary to
achieve significant improvement. Thus, there exists a great unmet
need in the art for a safe and efficacious (topical) treatment for
the cutaneous lesions associated with MCV infection.
[0066] Hydrogen peroxide (H.sub.2O.sub.2) is a compound that is
ubiquitous in the environment. It is the simplest peroxide and a
potent oxidizing agent commonly used in innumerable household goods
including chlorine-free bleaches, general-purpose cleaning
products, and disinfectants, has been employed as the oxidizing
component in hair dyes, and has been used in oral hygiene products
and tooth-whitening systems for many years. In industry, it is
employed in the treatment of wastewater and, in high
concentrations, it is used in bleaching paper, pulp, and textiles.
Clinically, in addition to its use as an oral topical agent noted
above, hydrogen peroxide is widely employed at low concentrations
(e.g., 3%-6%) as a wound irrigant and topical
antiseptic/disinfectant, and has been in use medicinally since its
introduction into clinical practice by Richardson in 1858.
[0067] Hydrogen peroxide is an important oxidizing agent in
biological systems. The local deleterious effects of reactive
oxygen species on the skin are mitigated by the presence of a
complex antioxidant defense system that includes, enzymes such as
catalase, glutathione peroxidase, superoxide dismutase, thioredoxin
reductase, lipoamine, lipid peroxidase and others, as well as
non-enzymatic components including ascorbic acid, urates and uric
acid, tocopherol, glutathione, ubiquinones, ubiquinol and other
water soluble groups. The local application of supra-physiologic
concentrations of hydrogen peroxide may overwhelm the antioxidant
defense systems in the skin, allowing hydrogen peroxide to act not
only through its direct oxidation of organic tissues, generation of
reactive oxygen species, and local lipid peroxidation, but also by
the generation of local concentrations of oxygen that are toxic to
the abnormal lesional (e.g., seborrheic keratosis, wart, condyloma
acuminatum, molluscum contagiosum) cells.
[0068] It has been unexpectedly observed that both seborrheic
keratosis lesions and common wart (verruca vulgaris) lesions
evidenced a clinical response after the application of the
compositions of embodiments herein. In certain cases, clearance of
the cutaneous lesion was observed after one single treatment. In
other cases, e.g., with thicker lesions or larger lesions, two or
more treatments may be required for a clinical response. As
exemplary benefits of this treatment method, the clinical response
was brought about without the need for analgesia, without inducing
pain, and without inducing the significant adverse events and
adverse cosmetic outcomes commonly resulting from other therapies
such as, e.g., pigmentary changes (such as hypopigmentation or
hyperpigmentation), scarring at the treatment site, bleeding or
infection.
[0069] Embodiments herein generally are directed to compositions
comprising hydrogen peroxide and a surface tension modifying agent.
In some embodiments, the surface tension modifying agent is an
agent stable in compositions comprising concentrations of hydrogen
peroxide disclosed in embodiments herein. In some embodiments, the
surface tension modifying agent is in a quantity sufficient to
enhance the therapeutic efficacy of the composition. In some
embodiments, the surface tension modifying agent is in a quantity
sufficient to enhance the therapeutic efficacy of the composition
while maintaining stability of the composition. In some
embodiments, the surface tension modifying agent is in a quantity
sufficient to enhance the therapeutic efficacy of the composition
while maintaining stability of the composition sufficient for use
as a commercially viable formulation. In some embodiments, the
surface tension modifying agent is an alcohol. Embodiments herein
are directed to compositions comprising hydrogen peroxide and an
alcohol. In some embodiments, the hydrogen peroxide may be a
standard grade, food grade, chemical synthesis grade, semiconductor
grade, high-test hydrogen peroxide grade, antimicrobial grade,
drinking water grade, pharmaceutical grade or cosmetic grade
hydrogen peroxide. In some embodiments, the alcohol may be selected
from a primary alcohol, a secondary alcohol, a tertiary alcohol, or
a combination thereof. In some embodiments, the alcohol may be
selected from, but is not limited to, a low molecular weight
alcohol, such as methanol, ethanol, butanol, 1-propanol, pentanol,
hexanol, octanol, nonanol, decanol, 2-butanol, 2-propanol,
2-pentanol, benzyl alcohol, an isomer thereof, or a combination
thereof. In some embodiments, the alcohol is not 1-propanol,
ethanol, propanol, butanol, pentanol, hexanol, octanol, nonanol,
decanol, 2-butanol, 2-pentanol, or benzyl alcohol. In some
embodiments, the alcohol is 2-propanol (also referred to as
isopropyl alcohol). In some embodiments, other volatiles such as,
for example, acetates such as ethyl and butyl acetate (volatiles
used in nail lacquers), cyclomethicone (a volatile silicone which
may be included in an emulsifier system) may be used in combination
with or in place of an alcohol. Embodiments herein also include a
composition consisting essentially of hydrogen peroxide and an
alcohol. Some embodiments are directed to a composition consisting
of hydrogen peroxide and an alcohol. Some embodiments are directed
to a composition comprising hydrogen peroxide and 2-propanol. Some
embodiments are directed to a composition consisting essentially of
hydrogen peroxide and 2-propanol. Some embodiments are directed to
a composition consisting of hydrogen peroxide and 2-propanol.
[0070] In some embodiments, the hydrogen peroxide is in an amount
of up to about 50% of the composition. In some embodiments, the
composition comprises hydrogen peroxide in an amount of about 0.5%
to about 99.9%, about 10% to about 99.9%, about 20% to about 99.9%,
about 30% to about 99.9%, about 40% to about 99.9%, about 50% to
about 99.9%, about 60% to about 99.9%, about 70% to about 99.9%,
about 80% to about 99.9%, about 90% to about 99.9%, about 0.5% to
about 70%, about 5% to about 70%, about 10% to about 70%, about 15%
to about 70%, about 20% to about 70%, about 25% to about 70%, about
30% to about 70%, about 35% to about 70%, about 40% to about 70%,
about 45% to about 70%, about 50% to about 70%, about 55% to about
70%, about 60% to about 70%, about 65% to about 70%, up to about
50%, about 0.5% to about 50%, about 5% to about 50%, about 10% to
about 50%, about 15% to about 50%, about 20% to about 50%, about
23.5% to about 50%, about 25% to about 50%, about 30% to about 50%,
about 35% to about 50%, about 40% to about 50%, or about 45% to
about 50%. In some embodiments, the hydrogen peroxide may be in an
amount of about 0.5%, 5%, 10%, 15%, 20%, 23.5%, 25%, 30%, 32.5%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or a range between any two
of these values.
[0071] In some embodiments, the hydrogen peroxide may be a
stabilized hydrogen peroxide. In some embodiments, the hydrogen
peroxide may be a standard grade, food grade, chemical synthesis
grade, semiconductor grade, high-test hydrogen peroxide grade,
antimicrobial grade, drinking water grade, pharmaceutical grade or
cosmetic grade hydrogen peroxide. In some embodiments, the hydrogen
peroxide may be a stabilized pharmaceutical grade hydrogen
peroxide. In some embodiments, the hydrogen peroxide may be a
stabilized cosmetic grade hydrogen peroxide. In some embodiments,
the hydrogen peroxide is FMC/PeroxyChem "Super D" 50% cosmetic
grade hydrogen peroxide. In some embodiments, the hydrogen peroxide
is FMC/PeroxyChem's "High-Test Hydrogen Peroxide," which includes
stabilized 50%, 70%, and 90% hydrogen peroxide. In some
embodiments, the hydrogen peroxide is Arkema Peroxal 50 CG. In some
embodiments, the starting hydrogen peroxide concentration is at a
concentration sufficient to be diluted to a concentration of about
23% hydrogen peroxide or above in the compositions described
herein. In some embodiments, the stabilized hydrogen peroxide has
stabilizers in a concentration sufficient to prevent the
breakdown/degradation of the hydrogen peroxide when it is diluted
to a concentration of about 23% hydrogen peroxide or above in the
compositions described herein. In some embodiments, the stabilized
hydrogen peroxide has stabilizers in a concentration sufficient to
prevent the breakdown/degradation of the surface-tension modifying
agent (e.g., alcohol such as 2-propanol) when it is diluted to a
concentration of about 23% hydrogen peroxide or above in the
compositions described herein. In some embodiments, the stabilized
hydrogen peroxide has stabilizers in a concentration sufficient to
ensure the stability of the composition to be packaged in an
appropriate packaging system, container, or applicator, and to be
suitable for commercial use as contemplated in embodiments
described herein. For example, in some embodiments, a method of
making the composition may comprise a step or steps that the
stabilized hydrogen peroxide be diluted down to, e.g., 45%, or 40%
or 32.5%, or 25%, in the final composition. In this scenario, the
starting hydrogen peroxide formulation should have a sufficiently
high concentration to be able to be diluted to, e.g., 45%, or 40%,
or 32.5%, or 25%, with the addition of water such as deionized
water and an additional excipient or excipients such as a
surface-tension modifying agent such as an alcohol (e.g.,
2-propanol, or the like), as described in embodiments herein, such
that it is sufficiently stabilized in order to guarantee a
shelf-life suitable to produce a commercially viable
formulation.
[0072] Hydrogen peroxide is a compound which is highly susceptible
to decomposition by the presence of dissolved impurities, mostly
transition metal cations and mixtures based on hydrogen peroxide
may be unstable, with the hydrogen peroxide concentration
diminishing over time due to catalytic decomposition. Impurities
causing hydrogen peroxide decomposition are typically contained in
water used to dilute the aqueous hydrogen peroxide stock
formulation to a desired concentration or in the additional
excipients added to the formulation (e.g., 2-propanol). A variety
of factors may influence the stability of hydrogen peroxide in
solutions, including, for example, the temperature, the
concentration of hydrogen peroxide, the pH value, and the presence
of impurities having a decomposing effect. To limit the influence
of such decomposing factors on stability, it has been discovered
that, in some embodiments, a stabilized composition having
commercial value for the treatment of the multiple skin conditions
described herein, e.g., seborrheic keratosis, warts, condyloma
acuminatum, molluscum contagiosum, may be achieved by the careful
selection of a concentration of 2-propanol and a stabilized (e.g.,
cosmetic grade) of high concentration (e.g., 50%) aqueous hydrogen
peroxide solution. Accordingly, in some embodiments, the
composition may comprise a stabilizer or combination of
stabilizers. Hydrogen peroxide products from different sources may
differ because of a proprietary blend of stabilizers unique to each
company and to each product line within each company, and may
importantly affect the stability and performance of the final
product. Stabilizer levels for each individual stabilizer may vary
from above 0 mg/ml to several thousand mg/1 each depending on the
grade of the hydrogen peroxide, the concentration of the peroxide,
and the choice of stabilizers used. In some embodiments, the
hydrogen peroxide is supplied by FMC Industrial Chemicals.RTM. (now
PeroxyChem, LLC.), Sigma Corporation.RTM., Arkema
Incorporated.RTM., or the like. In some embodiments, the hydrogen
peroxide is supplied by PeroxyChem, LLC. In some embodiments, the
hydrogen peroxide is FMC/PeroxyChem "Super D" 50% Cosmetic Grade
hydrogen peroxide. Common stabilizers included in hydrogen peroxide
formulations may include a stannate (e.g., colloidal stannate,
sodium stannate), sodium pyrophosphate, organophosphonates,
nitrate, phosphoric acid, colloidal silicate, any other stabilizer
known in the art, or a combination thereof. In some embodiments,
each stabilizer may be in a concentration of above 0 ppm to about
5000 ppm. In some embodiments, each stabilizer may be in a
concentration of above 0 ppm to about 3000 ppm. In some
embodiments, each stabilizer may be in a concentration of about 70
ppm to about 5000 ppm. In some embodiments, each stabilizer may be
in a concentration of about 70 ppm to about 3000 ppm. In some
embodiments, each stabilizer may be in a concentration of about 70
ppm to about 2700 ppm. In some embodiments, each stabilizer may be
in a concentration of about 270 ppm to about 5000 ppm. In some
embodiments, each stabilizer may be in a concentration of about 300
ppm to about 5000 ppm. In some embodiments, each stabilizer may be
in a concentration of about 270 ppm to about 3000 ppm. In some
embodiments, each stabilizer may be in a concentration of about 300
ppm to about 3000 ppm. In some embodiments, each stabilizer may be
in a concentration of about 300 ppm to about 2700 ppm. In some
embodiments, each stabilizer may be in a concentration of about 270
ppm to about 2700 ppm.
[0073] The hydrogen peroxide in compositions of embodiments herein
may be replaced with or combined with other peroxides. Other
peroxides may include, but are not limited to, sodium peroxide,
potassium peroxide and potassium superoxide, lithium peroxide,
barium peroxide, calcium peroxide, magnesium peroxide, zinc
peroxide, tert-butyl hydroperoxide, peracetic acid, dibenzyl
peroxide, benzoyl peroxide, lauroyl peroxide, or a combination
thereof.
[0074] Water, organic solvents such as alcohols, surfactants, and
other agents may alter the surface tension of compositions,
formulations, and most particularly of solutions. However, little
is known about the effects of low concentrations of alcohols or
other volatiles on the wettability of normal skin when
alcohol/water mixtures are applied, and there have been no reports
on the effects of different concentrations of alcohols or other
volatiles when incorporated into formulations comprising hydrogen
peroxide on the wettability of normal skin or of the wettability of
abnormal or lesional skin--such as skin that has been affected by
seborrheic keratosis, warts, condyloma accuminatum, molluscum
contagiosum, or other virally induced or non-virally induced
cutaneous growths or lesions, including those skin conditions
listed herein. Without being bound by theory, it is believed that
the inclusion of alcohol in a stabilized peroxide solution may
serve several important functions: The incorporation of a low
concentration of the alcohol, e.g., less than 15% 2-propanol, may
allow for the incorporation of a therapeutically effective
concentration of hydrogen peroxide (e.g., 25% to 45% hydrogen
peroxide), where the hydrogen peroxide may be in sufficient
concentration to achieve the desired therapeutic effect on the
cutaneous lesions, and the alcohol is in an amount sufficient to
decrease the surface tension of the formulation and to increase the
wettability of the surface of the skin lesion to allow spread of
the formulation over the surface and into the surface
irregularities of the lesion. However, secondary alcohols (e.g.,
isopropanol (IPA)) are expected to be inherently less stable in
high concentrations of hydrogen peroxide than primary alcohols (see
below), that is, 2-propanol is expected to be more readily oxidized
in high concentrations of hydrogen peroxide than is 1-propanol, and
the incorporation of low concentrations of a secondary alcohol
(IPA) in a concentration sufficient to fulfill the above
requirements (decrease surface tension/increase wettability of the
skin lesion/maintain or enhance therapeutic efficacy) and allow the
creation of a stable, commercially viable formulation was
challenging.
[0075] It was surprisingly discovered that 2-propanol, in an amount
that may be sufficient to decrease the surface tension of the
formulation, may increase the wettability of the surface of the
skin lesions, and may maintain or enhance the therapeutic effect of
the formulation on the conditions that are the subject of this
application, may be stably incorporated into a highly concentrated
hydrogen peroxide solution. As noted above, isopropanol, a
secondary alcohol, is expected to be more easily oxidized than
1-propanol, the primary alcohol in the presence of high
concentrations of hydrogen peroxide. The mechanism of the oxidation
of alcohols in high concentrations of hydrogen peroxide is first,
the generation of hydroxyl radicals from the decomposition of the
hydrogen peroxide. This process can be accelerated by the presence
of catalytic metals or other catalysts such as those that might be
introduced by the addition of excipients &/or impurities
(mainly transition metal cations). The hydroxyl radical would then
abstract a hydrogen atom from the carbon adjacent to the oxygen on
the alcohol molecule, resulting in a carbon radical. In the case of
isopropanol, this is a secondary radical which is stabilized by the
electrons on the oxygen and both methyl groups next to the carbon.
For 1-propanol, this is a primary radical with just one alkyl group
next to it, which is less stable and more difficult to form. This
intermediate would lose the hydrogen atom of the hydroxyl group to
form ketone or aldehyde and the aldehyde, propanal from 1-propanol,
can be further oxidized to propionic acid. In preparations of
hydrogen peroxides that are of high purity and are highly
stabilized or have high concentrations of stabilizers (and with
lower concentrations of catalyst/impurities), the decomposition of
peroxide may be slowed and thus the decomposition of the included
alcohol may be slowed. Though without an obvious catalyst, the
decomposition of peroxide is slow. The apparent reaction rate might
be complex equation involving any trace catalyst (e.g., catalytic
metal), peroxide and alcohol concentrations, but considering the
alcohol alone, a secondary alcohol is more easily oxidized than the
primary one. It was surprisingly discovered, however, that by
employing a stabilized formulation of hydrogen peroxide (e.g.,
FMC/PeroxyChem "Super D"), the incorporation of low concentrations
of the secondary alcohol 2-propanol (IPA) into a stable,
commercially viable formulation, was indeed possible. Additionally
and importantly, primary alcohols, such as 1-propanol are known to
provoke cutaneous erythema (redness) and irritation of the skin and
may produce a "flushing reaction" when applied to the skin due to
the generation of aldehyde intermediates of primary alcohol
breakdown. Alcohol dehydrogenase (ADH), which is present in the
skin, acts on and breaks down primary alcohols, such as 1-propanol,
but does not act on secondary alcohols, such as 2-propanol. Thus,
only primary alcohols, which can be oxidized to the corresponding
aldehydes by alcohol dehydrogenase (ADH) present in the skin, and
not secondary (or tertiary) alcohols, elicit this cutaneous
erythema reaction by this important mechanism. By incorporating a
secondary alcohol such as 2-propanol (rather than a primary alcohol
such as 1-propanol) into the composition, adverse cutaneous
erythematous reactions resulting from or exacerbated by ADH
catalyzed aldehyde intermediates may be avoided or mitigated.
[0076] It was thus surprisingly discovered that the addition of
lower concentrations of alcohol, such as those described in
embodiments herein, and particularly 2-propanol, to hydrogen
peroxide increased the wettability of the skin lesion.
Additionally, skin lesions, by nature, may have crevices and/or
invaginations or surface irregularities that may make penetration
of the hydrogen peroxide difficult. Accordingly, in some
embodiments, a composition may comprise a hydrogen peroxide and a
surface tension modifying agent. In some embodiments, the surface
tension modifying agent may be an alcohol. The alcohol may be in an
amount sufficient to decrease the surface tension of the
composition to a level that effectively increases the penetration
of the composition into such crevices and/or invaginations of the
skin lesion, increase the surface area of reaction and increase the
therapeutic efficacy and/or clinical response of the skin lesion to
the therapeutic composition. In some embodiments, the composition
further comprises another surface-tension modifying agent. In some
embodiments, the surface tension modifying agent may be selected
from, without limitation, a surfactant, e.g., an anionic or
nonionic surfactant, a water-soluble surfactant such as a
polysorbate, SLS (sodium lauryl sulfate), polypropylene glycol
(PPG) stearate such as Arlamol, PEG (polyethylene glycol) stearate,
steareth, ceteareth, polyoxyl stearate, or the like, or a
combination thereof. The surface tension modifying agent may be in
an amount sufficient to decrease the surface tension of the
composition to a level that effectively increases the penetration
of the composition into the crevices, invaginations and/or surface
irregularities of the skin lesion, increases the surface area of
reaction, and increases the therapeutic efficacy and/or clinical
response of the skin lesion to the therapeutic composition, or a
combination thereof.
[0077] In particular, it was surprisingly discovered that
2-propanol is a particularly effective alcohol for incorporation in
the compositions described herein. In fact, it was unexpectedly
discovered that 2-propoanol is a more suitable and effective
alcohol in the compositions described herein than 1-propanol.
1-propanol does allow for release of hydrogen peroxide, may reduce
the surface tension of the composition to increase penetration of
the composition into the skin, and was expected to be more stable
(i.e. less likely to be oxidized) in formulations comprising high
concentrations of hydrogen peroxide. In fact, when compared to
2-propanol, 1-propanol does, in some concentrations, provide
increased release or increased rate of release of hydrogen peroxide
and may reduce surface tension more (on a weight to weight basis).
However, it was surprisingly discovered that despite its seemingly
potential desirable effects, 1-propanol is actually a less
effective alcohol than 2-propoanol in compositions of embodiments
disclosed herein. Without wishing to be bound by theory, it is
believed that (i) though there is a trend towards 1-propanol
containing compositions to release more hydrogen peroxide where
1-propanol is in higher concentrations, 2-propanol containing
compositions effectively release hydrogen peroxide and exhibit a
more constant rate of release across the desired concentrations in
the embodiments described herein; (ii) though 1-propanol may reduce
the surface tension of the hydrogen peroxide formulation more, on a
weight for weight basis, than 2-propanol, the surface tension
reduction induced in the compositions of the preferred embodiments
by 1-propanol is excessive and suboptimal as it may induce such a
great reduction that the composition would undesirably spread off
the target lesion or area and onto surrounding non-lesional skin,
leading to adverse effects such as irritation and erythema due at
least in part to the generation of undesirable aldehyde
intermediates as discussed above; and (iii) though theoretically,
as discussed, the primary alcohol, 1-propanol, would be expected to
exhibit greater stability in high concentration hydrogen peroxide
formulations than the secondary alcohol (i.e. 2-propanol),
1-propanol appears to be oxidized to a greater degree by hydrogen
peroxide in the high concentration hydrogen peroxide formulations
of the preferred embodiments than is 2-propanol, and is, in fact,
less stable. Thus, the incorporation of 2-propanol in compositions
described herein provides for significant advantages over the
incorporation of 1-propanol, including, but not limited to,
providing for a therapeutically effective formulation which is more
stable--leading to improved clinical efficacy of the composition,
lower tendency to spread away from the intended site of application
and, therefore, a more favorable safety profile
[0078] The amount of alcohol in the composition may also be limited
by the peroxide concentration in the formulation. For example, if a
high concentration of peroxide is desired, the concentration of
alcohol may necessarily be lowered in order to maintain the high
concentration of peroxide in the formulation. In some embodiments,
the alcohol may be in an amount sufficient to decrease the surface
tension of the composition, to increase the penetration of the
composition into the crevices and/or invaginations of the skin
lesion, increase the surface area of reaction and increase the
therapeutic efficacy and/or clinical response of the skin lesion to
the therapeutic composition. In some embodiments, the formulation
does not spread undesirably onto the surrounding non-lesional
unaffected skin, which may occur with too large an amount of
alcohol or too great a reduction in surface tension. In some
embodiments the formulation does not irritate the surrounding,
non-lesional, unaffected skin. In some embodiments, the formulation
does not cause erythema to surrounding non-lesional unaffected
skin. Erythema and irritation of the surrounding, non-lesional,
unaffected skin may be caused by generation of irritating, erythema
inducing intermediates, such as aldehydes, which may be due to the
breakdown of suboptimal alcohols in the composition (e.g., primary
alcohols, such as 1-propanol).
[0079] In some embodiments, the composition comprises a surface
tension modifying agent. In some embodiments, the surface tension
modifying agent is an alcohol. In some embodiments, the surface
tension modifying agent is in an amount sufficient to decrease the
surface tension of the hydrogen peroxide and water formulation. In
some embodiments, the composition comprises an alcohol in an amount
sufficient to decrease the surface tension of the hydrogen peroxide
and water formulation. In some embodiments, the alcohol is a
primary alcohol, a secondary alcohol, a tertiary alcohol, or a
combination thereof. In some embodiments, the secondary alcohol is
2-propanol. Without alcohol, such as 2-propanol, to decrease the
surface tension, the hydrogen peroxide-water formulation may sit on
the surface of the lesion, without penetrating the lesion and/or
the surface imperfections, irregularities, crevices of the lesion.
In some embodiments, the surface tension modifying agent may be in
an amount sufficient to decrease the surface tension of the
composition to a level that effectively increases the penetration
of the composition into such crevices and/or invaginations of the
skin lesion, increase the surface area of reaction, increase the
therapeutic efficacy and/or clinical response of the skin lesion to
the therapeutic composition while minimizing irritation of the
surrounding skin, or any combination thereof. Furthermore, alcohols
that lower the surface tension of hydrogen peroxide composition
excessively may run the risk of easily spreading off the
application site and across non-lesional skin, causing less
activity at the needed site and unwanted irritation and other
adverse effects on the surrounding, unaffected skin.
[0080] In some embodiments, the alcohol in compositions of
embodiments herein may be replaced with other volatile agents. Such
volatile agents may include, but are not limited to, volatiles such
as acetates, e.g., ethyl acetate and butyl acetate (volatiles used
in nail lacquers), cyclomethicone (a volatile silicone which may be
included in an emulsifier system), and various other volatiles in
addition to those shown and described herein, which will become
apparent to those skilled in the art from the foregoing
description. Such additional volatile agents may be used in
combination with or in place of an alcohol.
[0081] In some embodiments, the alcohol may be selected from a
primary alcohol, a secondary alcohol, a tertiary alcohol, or a
combination thereof. In some embodiments, the alcohol may include
methanol, ethanol, butanol, 1-propanol, pentanol, hexanol, octanol,
nonanol, decanol, 2-butanol, 2-propanol, 2-pentanol, benzyl
alcohol, an isomer thereof or a combination thereof. In some
embodiments, the alcohol is 2-propanol. Though embodiments herein
may refer to 2-propanol in particular, one skilled in the art would
understand that other alcohols and/or volatiles, such as, but not
limited to, those described above may be used in place of
2-propanol in such embodiments.
[0082] 2-propanol (also referred to as isopropyl alcohol) is a
chemical compound with the molecular formula C.sub.3H.sub.8O or
C.sub.3H.sub.7OH. It is a colorless, flammable chemical compound
with a strong odor. It is the simplest example of a secondary
alcohol, where the alcohol carbon atom is attached to two other
carbon atoms sometimes shown as (CH.sub.3).sub.2CHOH. It is a
structural isomer of propanol. 2-propanol is miscible in water,
alcohol, ether and chloroform. It will dissolve ethyl cellulose,
polyvinyl butyral, many oils, alkaloids, gums and natural resins.
It is insoluble in salt solutions. Unlike ethanol or methanol,
2-propanol may be separated from aqueous solutions by adding a salt
such as sodium chloride, sodium sulfate, or any of several other
inorganic salts, since the alcohol is much less soluble in saline
solutions than in salt-free water. 2-propanol has many medical and
pharmaceutical uses and is typically used topically in
concentrations of about 60% to about 70% in water as a topical
disinfectant and in concentrations of about 60% to about 75% v/v
solution in gels as a hand sanitizer. 2-propanol is also used as a
water-drying aid for the treatment/prevention of otitis externa
(swimmer's ear) in a concentration of up to 95%.
[0083] In some embodiments, the alcohol is in an amount of up to
about 0.1%, up to about 0.25%, up to about 0.5%, up to about 1%, up
to about 2%, up to about 2.5%, up to about 3%, up to about 4%, up
to about 5%, up to about 8%, up to about 10%, up to about 14%, up
to about 15%, up to about 20%, or up to about 25% of the
composition. The use of low concentrations of alcohol, e.g.,
2-propanol, as described in embodiments herein, allows for the use
of stabilized hydrogen peroxides of therapeutically high
concentrations (such as greater than 23%) of hydrogen peroxide,
such that the stabilizers in the hydrogen peroxide are able to
maintain the chemical stability of the formulation without being
affected by the alcohol (and its impurities). In some embodiments,
the alcohol may comprise up to about 25% of the composition. In
some embodiments, the alcohol may be in an amount of about 0.05% to
about 25%, about 0.5% to about 25%, about 1% to about 25%, about
2.5% to about 25%, about 5% to about 25%, about 10% to about 25%,
about 15% to about 25%, or about 20% to about 25%, about 0.05% to
about 15%, about 0.5% to about 25%, up to about 5%, about 0.01% to
about 5%, about 0.1% to about 5%, about 0.5% to about 5%, about 1%
to about 5%, about 1.5% to about 5%, about 2% to about 5%, about
2.5% to about 5%, about 3% to about 5%, about 3.5%, to about 5%,
about 4% to about 5%, about 4.5% to about 5%, or the like. In some
embodiments, the alcohol may be in an amount of about 0.01%, 0.1%,
0.25%, 0.5%, 0.75%, 1%, 2%, 2.5%, 3%, 4% 5%, 10%, 15%, 20%, 25%, or
a range between any two of these values. In some embodiments, the
composition comprises about 40% hydrogen peroxide and about 5%
alcohol. In some embodiments, the composition comprises about 45%
hydrogen peroxide and about 5% alcohol. In some embodiments, the
composition comprises about 35% hydrogen peroxide and about 5%
alcohol. In some embodiments, the composition comprises about 32.5%
hydrogen peroxide and about 5% alcohol. In some embodiments, the
composition comprises about 25% hydrogen peroxide and about 5%
alcohol. In some embodiments, the composition comprises about 40%
hydrogen peroxide and about 2.5% alcohol. In some embodiments, the
composition comprises about 45% hydrogen peroxide and about 2.5%
alcohol. In some embodiments, the composition comprises about 35%
hydrogen peroxide and about 2.5% alcohol. In some embodiments, the
composition comprises about 32.5% hydrogen peroxide and about 2.5%
alcohol. In some embodiments, the composition comprises about 25%
hydrogen peroxide and about 2.5% alcohol. In some embodiments, the
composition comprises about 40% hydrogen peroxide and about 2%
alcohol. In some embodiments, the composition comprises about 45%
hydrogen peroxide and about 2% alcohol. In some embodiments, the
composition comprises about 35% hydrogen peroxide and about 2%
alcohol. In some embodiments, the composition comprises about 32.5%
hydrogen peroxide and about 2% alcohol. In some embodiments, the
composition comprises about 25% hydrogen peroxide and about 2%
alcohol. In some embodiments, the alcohol is 2-propanol.
[0084] In some embodiments, the composition consists essentially of
up to about 50% hydrogen peroxide and an alcohol. In some
embodiments, the composition consists essentially of about 40%
hydrogen peroxide and about 5% alcohol. In some embodiments, the
composition consists essentially of about 45% hydrogen peroxide and
about 5% alcohol. In some embodiments, the composition consists
essentially of about 35% hydrogen peroxide and about 5% alcohol. In
some embodiments, the composition consists essentially of about
32.5% hydrogen peroxide and about 5% alcohol. In some embodiments,
the composition consists essentially of about 25% hydrogen peroxide
and about 5% alcohol. In some embodiments, the composition consists
of up to about 50% hydrogen peroxide and an alcohol. In some
embodiments, the composition consists of about 40% hydrogen
peroxide and about 5% alcohol. In some embodiments, the composition
consists of about 45% hydrogen peroxide and about 5% alcohol. In
some embodiments, the composition consists of about 35% hydrogen
peroxide and about 5% alcohol. In some embodiments, the composition
consists of about 32.5% hydrogen peroxide and about 5% alcohol. In
some embodiments, the composition consists of about 25% hydrogen
peroxide and about 5% alcohol. In some embodiments, the alcohol is
2-propanol.
[0085] In some embodiments, the alcohol decreases the surface
tension of the composition. In some embodiments, the alcohol
increases the penetration of the hydrogen peroxide into the skin
imperfections of the subject, such as the irregularities, crevices
and imperfections of the skin or skin lesion. In some embodiments,
the alcohol defats the subject's skin or skin lesion of the
subject, thereby allowing better penetration of the hydrogen
peroxide into the subject's skin or skin lesion. In some
embodiments, the alcohol increases the wettability of the surface
of the skin, including the wettability of the skin growth or
lesion.
[0086] In some embodiments, the alcohol increases the effective
concentration of the hydrogen peroxide when administered. Hydrogen
peroxide is bactericidal, virucidal, sporocidal, and fungicidal,
and may be a sterilant at varying concentrations and contact times.
In some embodiments, the hydrogen peroxide is in a concentration
sufficient to be virucidal. In some embodiments the hydrogen
peroxide has sufficient contact time with the skin or skin lesion
for it to exhibit its bactericidal, virucidal, sporocidal,
fungicidal or sterilant effects. In some embodiments, the hydrogen
peroxide has sufficient contact time with the skin or skin lesion
sufficient for it to exhibit virucidal effects. Without being bound
by theory, the alcohol may increase the effective concentration of
the hydrogen peroxide when it evaporates after being administered,
and may increase the oxidative and/or germicidal activity of the
formulation. Additionally, the increased penetration of the
formulation may increase the surface area or contact time of the
solution with the skin or skin lesion and lead to enhanced effect
as a germicide or sterilant.
[0087] In some embodiments, the composition may be administered
topically. In some embodiments, the composition may be a solution.
In some embodiments, the composition may be in a gel formulation.
In some embodiments, the solution or gel formulation may be in two
or more parts to be admixed at or immediately before the time of
administration. In some embodiments, the composition may be in a
cream, lotion, ointment, foam, transdermal patch, powder, solid,
tape, paste or tincture. In some embodiments, the methods of
treating described in embodiments herein require only one single
application of the composition of embodiments herein. In some
embodiments, the methods of treating described in embodiments
herein require two or more applications of the composition of
embodiments herein. In some embodiments, the methods of treating
described in embodiments herein require multiple applications of
the composition of embodiments herein.
[0088] In some embodiments, the composition may further include a
pharmaceutically acceptable excipient. In some embodiments, the
composition may further include an emollient, an emulsifier, a
gelling agent, an additive, or a combination thereof. In some
embodiments, the additive may be selected from preservatives,
emulsion stabilizers, pH adjusters, chelating agents, viscosity
modifiers, anti-oxidants, surfactants, detergents, emollients,
opacifying agents, skin conditioners, buffers, or a combination
thereof.
[0089] Some embodiments herein are directed to a gel formulation
comprising hydrogen peroxide, and a gelling agent. In some
embodiments, the gel formulation may further comprise an alcohol.
In some embodiments, the gel formulation may further comprise a
pharmaceutically acceptable excipient. In some embodiments, the
gelling agent may be selected from Carbopol ETD 2020, Carbopol 980
NF, Carbopol 974P, Carbopol Ultrez 10, or the like. In some
embodiments, the gelling agent may be high molecular weight, cross
linked copolymers of acrylic acid and a hydrophobic comonomer or a
copolymer (e.g., Pemulen TR-1); Polycarbophil AA-1; PVP (polyvinyl
pyrrolidone); Eudragit; Poloxamer; Sepineo; Bentonite; Aerosil
(silicates); Hyaluronic Acids; cross-linked Hyaluronic Acids; a
combination thereof, or a compositional or chemical equivalent
thereof possessive of the qualities required for the composition of
embodiments described herein. In some embodiments, the gel
composition is kept in two-parts and mixed at or immediately before
the time of application. For example, the hydrogen peroxide and
2-propanol (first part) could be kept separate from the gelling
agent (second part) until the time of administration or immediately
before. As another example, the hydrogen peroxide, 2-propanol and
gelling agent could each be separated into three parts and mixed at
or immediately before the time of application. Additional parts may
be possible for additional excipients or such excipients may be
incorporated into existing parts. At or immediately before the time
of administration, the multi-part gel formulation may be mixed and
applied topically to the skin as a single gel formulation.
[0090] Some embodiments are directed to a gel formulation that may
be delivered in an applicator that mixes two or more components of
the gel formulation at or immediately before the time of
application. In some embodiments, the gel formulation compartment
applicator comprises at least one frangible compartment (e.g.,
gelling agent in the main compartment of the applicator, with the
peroxide in a glass ampule within or alongside that compartment).
Some exemplary applicators may include syringe-like applicators or
"double-barrel" applicators that can freshly mix (e.g., "vortex
mix") two or more components that need to be held in separate
compartments for stability reasons, but which can be mixed at or
immediately before the time of application.
[0091] In some embodiments, the composition further includes a
buffer. In some embodiments, the buffer may be selected from
triethanolamine, low pH buffers such as sodium acetate, citrate,
phosphate, glycine, hydrogen chloride, citrate and phosphate,
glycine and hydrogen chloride, the like, or a combination thereof.
In some embodiments, the buffer may be present in an amount of
about 0.001% to about 15%. In some embodiments, the buffer is
present in an amount of about 0.001%, 0.01%, 0.05%, 0.1%, 0.5%, 1%,
5%, 10%, 15%, or a range between any two of these values. In some
embodiments the buffer is present in any amount necessary to
optimally adjust the pH of the composition.
[0092] In some embodiments, the composition has a surface tension
of about 15 mNm-1 to about 80 mNm-1 at room temperature. In some
embodiments, the composition has a surface tension of about 20
mNm-1 to about 80 mNm-1, about 30 mNm-1 to about 80 mNm-1, about 40
mNm-1 to about 80 mNm-1, about 50 mNm-1 to about 80 mNm-1, about 35
mNm-1 to about 80 mNm-1, about 35 mNm-1 to about 70 mNm-1, about 35
mNm-1 to about 60 mNm-1, about 35 mNm-1 to about 50 mNm-1 at
37.degree. C., about 40 mNm-1 to about 80 mNm-1, about 40 mNm-1 to
about 70 mNm-1, about 40 mNm-1 to about 60 mNm-1, about 40 mNm-1 to
about 50 mNm-1, about 45 mNm-1 to about 80 mNm-1, about 45 mNm-1 to
about 70 mNm-1, about 45 mNm-1 to about 60 mNm-1, or about 45 mNm-1
to about 50 mNm-1 at room temperature. In some embodiments, the
composition has a surface tension of about 15 mNm-1, about 20
mNm-1, about 30 mNm-1, about 36 mNm-1, about 41 mNm-1, about 48
mNm-1, about 54 mNm-1, about 75 mNm-1, about 40 mNm-1, about 50
mNm-1, about 60 mNm-1, about 70 mNm-1, about 80 mNm-1, or a range
between any two of these values at room temperature. In some
embodiments, the composition has a surface tension of about 42
mNm-1 to about 55 mNm-1 at room temperature. In some embodiments,
the composition has a surface tension of about 42 mNm-1 to about 50
mNm-1 at room temperature.
[0093] In some embodiments, the composition has a surface tension
of about 15 mNm-1 to about 80 mNm-1 at 37.degree. C. In some
embodiments, the composition has a surface tension of about 20
mNm-1 to about 80 mNm-1, about 30 mNm-1 to about 80 mNm-1, about 40
mNm-1 to about 80 mNm-1, about 50 mNm-1 to about 80 mNm-1, about 35
mNm-1 to about 80 mNm-1, about 35 mNm-1 to about 70 mNm-1, about 35
mNm-1 to about 60 mNm-1, about 35 mNm-1 to about 50 mNm-1 at
37.degree. C., about 40 mNm-1 to about 80 mNm-1, about 40 mNm-1 to
about 70 mNm-1, about 40 mNm-1 to about 60 mNm-1, about 40 mNm-1 to
about 50 mNm-1, about 45 mNm-1 to about 80 mNm-1, about 45 mNm-1 to
about 70 mNm-1, about 45 mNm-1 to about 60 mNm-1, or about 45 mNm-1
to about 50 mNm-1 at 37.degree. C. In some embodiments, the
composition has a surface tension of about 15 mNm-1, about 20
mNm-1, about 30 mNm-1, about 36 mNm-1, about 41 mNm-1, about 48
mNm-1, about 54 mNm-1, about 75 mNm-1, about 40 mNm-1, about 50
mNm-1, about 60 mNm-1, about 70 mNm-1, about 80 mNm-1, or a range
between any two of these values at 37.degree. C. In some
embodiments, the composition has a surface tension of about 42
mNm-1 to about 55 mNm-1 at 37.degree. C. In some embodiments, the
composition has a surface tension of about 42 mNm-1 to about 50
mNm-1 at 37.degree. C.
[0094] In some embodiments, a composition comprising 40% hydrogen
peroxide has a surface tension of from about 35 mNm-1 to about 60.3
mNm-1 at 37.degree. C. In some embodiments, a composition
comprising 40% hydrogen peroxide may have a surface tension of
about 60.3 mNm-1 at 37.degree. C. A composition comprising 40%
hydrogen peroxide and 2.5% 2-propanol may have a surface tension of
about 54.1+/-0.8 mNm-1 at 37.degree. C. A composition comprising
40% hydrogen peroxide and 5% 2-propanol may have a surface tension
of about 48.3+/-0.7 mNm-1 at 37.degree. C. A composition comprising
40% hydrogen peroxide and 10% 2-propanol may have a surface tension
of about 41.1+/-0.6 mNm-1 at 37.degree. C. A composition comprising
40% hydrogen peroxide and 15% 2-propanol may have a surface tension
of about 35.9+/-0.6 mNm-1 at 37.degree. C.
[0095] In some embodiments, the composition has a pH of about 1.5
to about 7.0. In some embodiments, the pH may be about 1.5 to about
3.5, about 1.5 to about 5.0, about 1.5 to about 4.0, about 1.7 to
about 3.7, about 2.0 to about 5.0, about 2.0 to about 4.0, about
2.0 to about 2.8, about 2.5 to about 4.0, about 2.5 to about 4.5,
about 2.5 to about 5.0, about 2.7 to about 3.83, about 2.7 to about
4.0, about 2.8 to about 4.0, about 2.83 to about 3.83, about 3.0 to
about 7.0, about 4.0 to about 7.0, about 5.0 to about 7.0, or about
6.0 to about 7.0. In some embodiments, the pH may be about 1.5,
1.7, 2.0, 2.5, 2.7, 2.8, 2.83, 3.0, 3.3, 3.5, 3.7, 3.83, 4.0, 4.5,
5.0, 5.5, 6.0, 6.5, 7.0, or a range between any two of these
values.
[0096] In some embodiments, the compositions of embodiments herein
are stable for up to about four weeks at room temperature. In some
embodiments, the compositions of embodiments herein are stable for
up to about 15 minutes, about 30 minutes, about 1 hour, about 2
hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours,
up to about 12 hours, up to about 24 hours, up to about 1 week, up
to about 2 weeks, up to about 3 weeks, up to about 1 month, up to
about 6 weeks, up to about 2 months, up to about 3 months, up to
about 4 months, up to about 6 months, up to about 8 months, up to
about 10 months, up to about 12 months, up to about 18 months, up
to about 2 years, up to about 2.5 years, or up to about 3 years at
room temperature. In some embodiments, the compositions of
embodiments herein are stable for up to about four weeks, up to
about six weeks, up to about eight weeks, up to about three months,
up to about 6 months, up to about 8 months, or up to about a year
at 40.degree. C. In some embodiments, the compositions of
embodiments herein are stable for up to about four weeks, up to
about 6 weeks, up to about 1 month, up to about 2 months, up to
about 3 months, up to about 4 months, up to about 6 months, up to
about 8 months, up to about 10 months, up to about 12 months, up to
about 18 months, up to about 2 years, up to about 2.5 years, or up
to about 3 years at 30.degree. C. In some embodiments, the
compositions of embodiments herein are stable for up to about four
weeks, up to about 1 month, up to about 6 weeks, up to about 2
months, up to about 3 months, up to about 4 months, up to about 6
months, up to about 8 months, up to about 10 months, up to about 12
months, up to about 18 months, up to about 2 years, up to about 2.5
years, or up to about 3 years at 25.degree. C. In some embodiments,
the compositions of embodiments herein are stable for up to about
four weeks, up to about 6 weeks, up to about 1 month, up to about 2
months, up to about 3 months, up to about 4 months, up to about 6
months, up to about 8 months, up to about 10 months, up to about 12
months, up to about 18 months, up to about 2 years, up to about 2.5
years, or up to about 3 years at 5.degree. C.
[0097] In some embodiments, the compositions of embodiments herein
satisfy the stability requirements put forth by the International
Conference of Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use in the "ICH
Harmonised Tripartite Guideline: Stability Testing of New Drug
Substances and Products Q1A(R2)", current Step 4 version, dated 6
Feb. 2003, the entirety of which is incorporated herein by
reference.
[0098] In some embodiments, the compositions of embodiments herein
may also be administered in combination with other methods that
mechanically, physically or chemically enhance the penetration of
the active into the lesion. Such methods may include
tape-stripping, destructive/ablative modalities such as, e.g.,
liquid nitrogen cryotherapy, electrodesiccation, lasers of various
wavelengths (ablative and non-ablative), radio-frequency ablation,
dermabrasion, and partial or complete surgical removal by curettage
or surgical excision, use of an ablative or chemical peeling agent,
or otherwise disturbing the surface of, or decreasing the thickness
or size or overall volume of, or increasing the surface area of the
lesion. In some embodiments, the compositions of embodiments herein
may be administered in combination with other active ingredients,
such as, for example, adjuvants, inhibitors, or other compatible
drugs or compounds where such combination is seen to be desirable
or advantageous in achieving the desired effects of the methods
described herein. Any other known treatment may be used in
combination with the formulation to treat the skin diseases
disclosed herein. For example, the composition may be administered
in combination with an active pharmaceutical agent that is used to
treat the skin conditions described herein. In some embodiments,
the compositions of embodiments herein may be administered before,
concomitant with, or after the administration of another compound
to treat the lesion. In some embodiments, the composition further
comprises a topically active pharmaceutical agent used to treat the
skin conditions described herein. As an example, a method of
treating seborrheic keratosis may comprise administering ingenol
mebutate to the subject and then administering the compositions of
embodiments herein. As another example, a method of treating warts
may comprise administering salicylic acid to the lesion of a person
in need thereof in the morning and administering a composition of
embodiments herein to the lesion of a person in need thereof in the
evening. As another example, a method of treating warts, seborrheic
keratosis, condyloma acuminate, mollusca, or acrochordons may
comprise administering a topical retinoid to the lesion of a person
in need thereof for a number of days and administering a
composition of embodiments herein to the lesion of a person in need
thereof after a number of days of pretreatment with the topical
agent. Other possible examples will be readily apparent to one
knowledgeable in the art. The other active or procedure may be
administered or performed either before, after or concurrently with
the compositions of embodiments herein.
[0099] Embodiments herein are also directed to a method of treating
a skin condition comprising administering a composition of
embodiments herein to a subject in need thereof. In some
embodiments, the composition may be administered once daily, twice
daily, weekly, biweekly, three times a week, every other day,
monthly, every two months, every three months or as directed by the
packaging or the physician to achieve the desired clinical result.
The skin condition may be of infectious etiology. The skin
condition may be a virally induced or non-virally induced cutaneous
growth or proliferation. The skin condition may be a benign
neoplasm, premalignancy or malignancy. The skin condition may be an
inflammatory condition. The skin condition may be a
hyperproliferative condition. The skin condition may be ageing
including intrinsic and extrinsic changes (e.g., photoaging
(ultraviolet light induced changes)), pigmentary changes, fine
lines and rhytides. In some embodiments, the skin condition may be
selected from Human Papilloma Virus induced lesions e.g., warts,
common warts, recurrent warts, recalcitrant warts, treatment naive
warts, palmoplantar warts, flat warts, epidermodysplasia
verruciformis related warts, anogenital warts, condyloma
accuminatum, cervical dysplasias or neoplasias, e.g., cervical
intraepithelial neoplasia (CIN); Herpesvirus related lesions
including those induced by HHV-1 (HSV-1), HHV-2 (HSV-2), HHV-3
(varicella-zoster virus) e.g., chicken pox, Herpes zoster,
shingles; Poxvirus induced lesions e.g., molluscum contagiosum,
orf, callus, cutaneous horns, corns, acrochordons, fibroepithelial
polyps, prurigo nodularis, actinic keratoses, squamous cell
carcinoma, squamous cell carcinoma in situ, keratoacanthoma, basal
cell carcinoma, cutaneous lymphomas and benign lymphocytic
infiltrates & hyperplasias of the skin, clear cell acanthoma,
large cell acanthoma, epidermolytic acanthoma, porokeratosis,
hyperkeratosis, keratosis pilaris, lichenoid keratosis, acanthosis,
acanthosis nigricans, confluent and reticulated papillomatosis,
nevi, including e.g., dermal nevi, epidermal nevi, compound nevi,
ILVEN (inflammatory linear verrucous epidermal nevi), nevus
sebaceous, nevus comedonicus, and the like; acne, e.g., comedonal
acne, inflammatory acne, papular acne, pustular acne, cystic acne;
cysts, e.g., epidermoid cysts, milia, trichilemmal cysts,
follicular cysts, proliferating cysts, dermoid cysts, pilonidal
cysts, apocrine cysts, eccrine cysts, sebaceous cysts, mucous
cysts, myxoid cysts, ganglion cysts, synovial cysts, vellus hair
cysts, steatocystoma, hidrocystoma; adnexal neoplasms e.g.,
trichofolliculoma, fibrofolliculoma, perifollicular fibroma,
trichodiscoma, nevus sebaceous, chondroid syringoma,
trichoepithelioma, trichoblastoma, desmoplastic trichoepithelioma,
pilomatricoma, pilomatrical carcinoma, tricholemmoma, trichelemmal
carcinoma, tumor of the follicular infundibulum, tricoadenoma,
proliferating pilar tumor, sebaceous hyperplasia, sebaceous
adenoma, sebaceous epithelioma, sebaceous carcinoma, syringoma,
poroma, hidradenoma, apocrine hidradenoma, spiradenoma, cylindroma,
eccrine nevus (eccrine hamartoma), papillary adenoma, papillary
adenocarcinoma; benign melanocytic proliferations or neoplasms
e.g., ephilides, cafe-au-lait macules, Becker's melanosis,
lentigines, solar lentigines, lentigo simplex, mucosal melanocytic
lesions, Mongolian spots, Nevus of Ota, blue nevus, common acquired
melanocytic nevi (nevocellular nevus, "moles"), congenital nevi,
nevus spilus, recurrent nevi; vascular and perivascular neoplasms
and reactive hyperplasias e.g., hemangiomas, cherry angiomas,
hobnail hemangiomas (targeted hemosiderotic hemangiomas), tufted
angiomas, hemangioendotheliomas, angiolymphoid hyperplasia with
eosinophilia (ALHE), Glomus tumors (glomangiomas),
hemangiopericytomas; cutaneous neural and neuroendocrine neoplasms
e.g., neuromas, Schwannomas, neurofibromas, nerve sheath tumor,
nerve sheath myxoma, neurothekeoma, granular cell tumor; fibrotic
and fibrohistiocytic proliferations e.g., acrochordons,
fibroepithelial polyps, fibromas, fibrous papules, angiofibromas,
pearly penile papules, periungual fibromas, dermatofibromas,
fibrokeratomas, sclerotic or pleomorphic fibromas, connective
tissue nevi; cutaneous scars, hyperplasias, keloids, rosacea,
cutaneous fungal, dermatophyte & mold infections,
onychomycosis, hyperpigmentation, psoriasis, malignant melanoma,
seborrheic keratosis, seborrheic keratosis variants including e.g.,
dermatosis papulosis nigra, inverted follicular keratosis/keratoma
warty dyskeratosis/warty dyskeratoma, acrokeratosis verruciformis,
stucco keratosis; or a combination thereof.
[0100] In some embodiments, the method of treating a skin condition
further comprises the step of cleansing the treatment site before
administration of the composition. In some embodiments, cleansing
the treatment site comprises defatting the treatment site before
the administration of the composition. In some embodiments
cleansing the treatment site comprises applying at least 70%
2-propanol to the skin to be treated before administration of the
composition. Defatting the treatment site may comprise applying the
alcohol onto the skin, such as by rubbing, massaging, placing,
scrubbing, abrading, wiping, swabbing, or otherwise contacting the
skin with the alcohol.
[0101] In some embodiments, the method of treating a skin condition
further comprises the step of debriding the treatment site of the
subject. In some embodiments, debriding may include mechanically,
chemically, or physically abrading, ablating, thinning, curetting,
destroying, removing, excising, or otherwise disturb the surface of
the skin or lesion to be treated, including decreasing the
thickness of, and/or decreasing the volume of the lesion. In some
embodiments, the step of debriding is before, after, and/or
concurrent with administration of the compositions of embodiments
herein to the treatment site.
[0102] In some embodiments, the alcohol may be selected from a
primary alcohol, a secondary alcohol, a tertiary alcohol, or a
combination thereof. The alcohol may be selected from methanol,
ethanol, butanol, 1-propanol, pentanol, hexanol, octanol, nonanol,
decanol, 2-butanol, 2-propanol, 2-pentanol, 2-hexanol, benzyl
alcohol, an isomer thereof, or a combination thereof. In some
embodiments, defatting the skin may comprise applying another known
defatting agent to the skin such as ethyl acetate, butyl acetate,
or the like onto the skin, such as by rubbing, massaging, placing,
scrubbing, abrading, wiping, swabbing, or otherwise contacting the
skin with the agent. In some embodiments, cleansing the skin
comprises applying an antiseptic solution to the skin or skin
lesion to be treated. In some embodiments, the antiseptic is
povidone, iodine, chlorhexidine, a detergent, soap or the like.
[0103] Some embodiments are directed to a method of treating warts
comprising administering a composition of embodiments herein to a
subject in need thereof. In some embodiments, the composition
comprises an alcohol and up to about 50% hydrogen peroxide. In some
embodiments, warts may be treated using any of the methods of
treatment described herein. Some embodiments are directed to a
method of improving the appearance of warts comprising
administering a composition of embodiments herein to a subject in
need thereof. Some embodiments are directed to a method of
improving the appearance of warts comprising administering a
composition of embodiments herein to a subject in need thereof.
Some embodiments are directed to a method of alleviating, e.g.,
shrinking, reducing in size, and/or reducing in height, a wart
comprising administering a composition of embodiments herein to a
subject in need thereof. In some embodiments, the warts are
treatment naive. In some embodiments, a treatment naive wart may be
treated using any of the methods of treatment described herein.
Some embodiments are directed to a method of improving the
appearance of treatment naive warts comprising administering a
composition of embodiments herein to a subject in need thereof.
Some embodiments are directed to a method of improving the
appearance of treatment naive warts comprising administering a
composition of embodiments herein to a subject in need thereof.
Some embodiments are directed to a method of alleviating, e.g.,
shrinking, reducing in size, and/or reducing in height, a treatment
naive wart comprising administering a composition of embodiments
herein to a subject in need thereof. In some embodiments, the warts
are recalcitrant warts. Recalcitrant warts may include warts that
are resistant to or have failed or have partially responded to
other therapies, warts that are difficult to treat, or warts that
are in anatomically difficult locations. In some embodiments,
recalcitrant warts may include plantar warts, periungal warts,
subungal warts or the like. In some embodiments, recalcitrant warts
may be located on any body surface. In some embodiments,
recalcitrant warts may be treated using any of the methods of
treatment described herein. Some embodiments are directed to a
method of improving the appearance of recalcitrant warts comprising
administering a composition of embodiments herein to a subject in
need thereof. Some embodiments are directed to a method of
improving the appearance of recalcitrant warts comprising
administering a composition of embodiments herein to a subject in
need thereof. Some embodiments are directed to a method of
alleviating, e.g., shrinking, reducing in size, and/or reducing in
height, a recalcitrant wart comprising administering a composition
of embodiments herein to a subject in need thereof. In some
embodiments, the composition comprises about 25% hydrogen peroxide
and 5% 2-propanol. In some embodiments, the composition comprises
about 32.5% hydrogen peroxide and 5% 2-propanol. In some
embodiments, the composition comprises about 40% hydrogen peroxide
and 5% 2-propanol. In some embodiments, the composition comprises
about 45% hydrogen peroxide and 5% 2-propanol. In some embodiments,
the composition comprises up to about 50% hydrogen peroxide and
2-propanol.
[0104] Some embodiments are directed to a method of treating
seborrheic keratosis comprising administering a composition of
embodiments herein to a subject in need thereof. In some
embodiments, the composition comprises an alcohol and up to about
50% hydrogen peroxide. In some embodiments, the composition
comprises about 45% hydrogen peroxide and 5% 2-propanol. In some
embodiments, the composition comprises about 40% hydrogen peroxide
and 5% 2-propanol. In some embodiments, the composition comprises
about 35% hydrogen peroxide and about 5% 2-propanol. In some
embodiments, the composition comprises about 32.5% hydrogen
peroxide and about 5% 2-propanol. In some embodiments, the
composition comprises about 25% hydrogen peroxide and about 5%
2-propanol.
[0105] Some embodiments are directed to a method of treating
acrochordons comprising administering a composition of embodiments
herein to a subject in need thereof. In some embodiments, the
composition comprises an alcohol and up to about 50% hydrogen
peroxide. In some embodiments, the composition comprises about 45%
hydrogen peroxide and 5% 2-propanol. In some embodiments, the
composition comprises about 40% hydrogen peroxide and 5%
2-propanol. In some embodiments, the composition comprises about
35% hydrogen peroxide and about 5% 2-propanol. In some embodiments,
the composition comprises about 32.5% hydrogen peroxide and about
5% 2-propanol. In some embodiments, the composition comprises about
25% hydrogen peroxide and about 5% 2-propanol.
[0106] Some embodiments herein are directed to a method of treating
a skin condition comprising (i) topically administering a first
dose of a composition comprising up to about 50% hydrogen peroxide
and an alcohol; and (ii) topically administering one or more
follow-up doses of the composition. In some embodiments, the
application of the first dose and one or more follow-up doses
comprises one application session. In some embodiments, the
follow-up dose is administered immediately after administration of
the first dose. In some embodiments, the follow-up dose is
administered at least about 0.5 minutes after the first dose. In
some embodiments, the follow-up dose is administered at least about
1 minute, at least about 1.5 minutes, at least about 2 minutes, at
least about 5 minutes, at least about 10 minutes, at least about 15
minutes, at least about 20 minutes, at least about 25 minutes, at
least about 30 minutes, or at least about 1 hour after the first
dose. In some embodiments, there may be one follow-up dose, two
follow-up doses, three follow-up doses, four follow-up doses, five
follow-up doses, six follow-up doses, seven follow-up doses, eight
follow-up doses, nine follow-up doses or ten follow-up doses in
each application session. Each subsequent follow-up dose may be
administered immediately after administration of the previous dose,
at least about 1 minute, at least about 1.5 minutes, at least about
2 minutes, at least about 5 minutes, at least about 10 minutes, at
least about 15 minutes, at least about 20 minutes, at least about
25 minutes, at least about 30 minutes or at least one hour after
the previous dose.
[0107] In some embodiments, the topical composition may be
administered in an effective dose. In some embodiments, an
effective dose may be from about 0.0025 milliliters to about 3
milliliters of the compositions of embodiments herein, including
about 0.0025 milliliters, about 0.01 milliliters, about 0.025
milliliters, about 0.05 milliliters, about 0.075 milliliters, about
0.1 milliliters, about 0.15 milliliters, about 0.5 milliliters,
about 1 milliliters, about 1.5 milliliters, about 2 millimeters,
about 2.5 milliliters, about 3 milliliters, a combination thereof,
or any amount that has a clinical effect on the lesion. In some
embodiments, the effective dose is proportional to size of the
lesion. In some embodiments, the effective dose of the composition
is less than about 0.1 milliliters per lesion. In some embodiments,
an effective dose may be about 3 milliliters of the compositions of
embodiments herein. In some embodiments, an effective dose may be
from about 2 milliliters to about 3 milliliters of the compositions
of embodiments herein. In some embodiments, an effective dose may
be from about 2 milliliters to about 5 milliliters of the
compositions of embodiments herein.
[0108] In some embodiments, topical administration of the first
dose and the follow-up doses comprises massaging the composition
into the skin for at least about 5 seconds, at least about 10
seconds, at least about 15 seconds, at least about 20 seconds, at
least about 25 seconds, at least about 30 seconds, at least about
35 seconds, at least about 40 seconds, at least about 45 seconds,
at least about 50 seconds, at least about 55 seconds, at least
about 1 minute, at least about 2 minutes, at least about 3 minutes,
at least about 4 minutes, or at least about 5 minutes, at least
about 10 minutes, at least about 15 minutes, at least about 20
minutes at least about 25 minutes, or at least about 30 minutes
during each dose. In some embodiments, the composition is a
solution. In some embodiments, the composition is a gel. In some
embodiments, massaging includes rubbing-in, manipulating, kneading,
pressing, or otherwise "working" the composition into the skin. In
some embodiments, the composition is applied and massaged into the
skin with an applicator. In some embodiments, the composition is
applied and massaged into the skin at least 1 time, at least 2
times, at least 3 times, at least 4 times, at least 5 times, at
least 6 times, at least 7 times, at least 8 times, at least 9
times, or at least 10 times in each application session. In some
embodiments, the application session, in which the composition is
administered, may be repeated once daily, twice daily, weekly,
biweekly, three times a week, every other day, monthly, every two
months, every three months, every six months or as directed by the
packaging or the physician to achieve the desired clinical
result.
[0109] In some embodiments, the composition is administered by a
health care provider. In some embodiments, the composition is
administered in a health care setting. In some embodiments, the
composition is self-administered by the subject in need thereof. In
some embodiments, the composition is administered by a caregiver of
the subject. As used herein, health care provider may include
doctor, nurse, physician's assistant, nurse practitioner, medical
assistant, or any professional working in a doctor's office,
hospital or clinic. A health care setting, as used herein, refers
to a doctor's office, hospital, ambulatory care setting, or clinic.
A caregiver of the subject may include parents, nurse, friend,
family member, medical professional, or anybody assisting in
administering the composition to the subject in need thereof.
[0110] In some embodiments, the method further comprises topically
administering a second composition comprising hydrogen peroxide and
alcohol as described in embodiments above to the subject following
an initial treatment by a health care provider. In some
embodiments, the second composition is a take home composition. In
some embodiments, the second composition is available over the
counter. In some embodiments, the second composition is available
by prescription. In some embodiments, the second composition may
comprise a lower concentration of hydrogen peroxide than the
initial treatment administered to the subject. In some embodiments,
the second composition may comprise the same concentration of
hydrogen peroxide as the initial treatment administered to the
subject. In some embodiments, the second composition comprises up
to about 50% hydrogen peroxide and an alcohol. In some embodiments,
the second composition comprises about 45% hydrogen peroxide and 5%
alcohol. In some embodiments, the second composition comprises
about 40% hydrogen peroxide and 5% alcohol. In some embodiments,
the second composition comprises about 35% hydrogen peroxide and 5%
alcohol. In some embodiments, the second composition comprises
about 32.5% hydrogen peroxide and 5% alcohol. In some embodiments,
the second composition comprises about 25% hydrogen peroxide and 5%
alcohol. In some embodiments, the alcohol is 2-propanol. In some
embodiments, the second composition may be self-administered by the
subject. In some embodiments, the second composition may be
administered at least about 1 day, at least about 2 days, at least
about 3 days, at least about 1 week, at least about 2 weeks, at
least about 3 weeks, at least about 4 weeks, at least about 5
weeks, at least about 6 weeks, at least about 7 weeks or at an
interval required to maintain the clinical effect or until the
lesion is cleared, after the initial treatment by the healthcare
professional. In some embodiments, the second composition may be
administered once daily, twice daily, weekly, biweekly, every other
day, monthly, every two months, every three months, every six
months, or as directed by the packaging or the physician to achieve
the clinically desired result.
[0111] Some embodiments herein are directed to a method of treating
a skin condition in a subject comprising topically administering a
take home composition comprising hydrogen peroxide and alcohol as
described above to the subject. In some embodiments, the take home
composition is available over the counter. In some embodiments, the
take home composition is available by prescription. In some
embodiments, the take home composition comprises about 50% hydrogen
peroxide and an alcohol. In some embodiments, the take home
composition comprises about 45% hydrogen peroxide and 5% alcohol.
In some embodiments, the take home composition comprises about 40%
hydrogen peroxide and 5% alcohol. In some embodiments, the take
home composition comprises about 35% hydrogen peroxide and 5%
alcohol. In some embodiments, the take home composition comprises
about 32.5% hydrogen peroxide and 5% alcohol. In some embodiments,
the take home composition comprises about 25% hydrogen peroxide and
5% alcohol. In some embodiments, the alcohol is 2-propanol. Such
take home compositions may be administered following a visit to a
healthcare professional. In some embodiments, the take home
composition may be administered following an initial treatment by a
healthcare professional. In some embodiments, the take home
composition may comprise a lower concentration of hydrogen peroxide
than the initial treatment administered to the subject. In some
embodiments, the take home composition may comprise the same
concentration of hydrogen peroxide as the initial treatment
administered to the subject. The take home composition may be
self-administered by the subject. In some embodiments, the take
home composition may be administered at least about 1 day, at least
about 2 days, at least about 3 days, at least about 1 week, at
least about 2 weeks, at least about 3 weeks, at least about 4 weeks
after the initial treatment by the healthcare professional. In some
embodiments, the take home composition may be administered once
daily, twice daily, weekly, biweekly, every other day, monthly,
every two months, every three months, every six months, or as
directed by the packaging or the physician to achieve the
clinically desired result.
[0112] Embodiments herein also encompass devices for administering
the hydrogen peroxide compositions of embodiments herein (see, for
example, FIGS. 12-16 and associated description). In some
embodiments, a composition comprising hydrogen peroxide and alcohol
as described in embodiments herein may be administered using any
topical applicator known in the art. In some embodiments, a
composition comprising hydrogen peroxide and alcohol as described
in embodiments herein may be administered using a sponge, a swab, a
foam tipped stick, a cotton ball, a brush, a woven or non-woven
fabric, roller, gauze, a pen, a glove, or the like. In some
embodiments, the applicator may dispense compositions of
embodiments herein via a tip that is flocked, absorbent, and/or
firm enough to apply pressure to the lesion. In some embodiments
the applicator is a sintered polymeric-tip applicator. In some
embodiments, the applicator is resistant to, compatible with, or
inert to high concentration peroxide solutions. In some
embodiments, the applicator is capable of dispensing the solution
at a controlled rate in order to help confine the active to the
lesion of interest and spare surrounding normal skin. In some
embodiments, the solution may be administered using a device having
the hydrogen peroxide solution in a compartment that dispenses the
solution onto or through an applicator tip when needed. In some
embodiments, the applicator may comprise a material designed to
abrade the skin lesion or treatment site before, after, or at the
time of administration of the composition. In some embodiments, the
applicator is a doe footed applicator. In some embodiments, the
applicator is a flocked, doe footed applicator. In some
embodiments, the flocked, doe footed applicator is comprised of
HDPE (high density polyethylene), nylon, and an adhesive. In some
embodiments, the solution is applied once daily, twice daily,
weekly, biweekly, three times a week, every other day, monthly,
every two months, every three months or as directed by the
packaging or the physician or provider to achieve the desired
clinical result.
[0113] In some embodiments, a method of treating a skin condition
comprises administering the composition of embodiments herein. In
some embodiments, administering the composition of embodiments
herein comprises contacting a treatment site with a tip of an
applicator, wherein the applicator comprises a frangible ampoule
having the composition disposed therein, an applicator body having
the frangible ampoule arranged therein, an applicator hub in fluid
communication with the applicator body, the tip arranged at a
proximal end of the applicator hub, and a filter arranged between
the frangible ampoule and the tip. In some embodiments,
administering the topical composition comprises controlling a flow
rate of the topical composition out of the tip by varying a
squeezing force applied to the exterior surface of the applicator
body. In some embodiments, administering the topical composition
comprises contacting the tip with a targeted lesion of the skin
condition whereby the topical composition dispenses through the tip
onto the targeted lesion. In some embodiments, administering the
topical composition further comprises applying pressure to a
pressure area arranged on an outer surface of the applicator body
causing the frangible ampoule to rupture. In some embodiments,
administering the topical composition comprises causing the
frangible ampoule to rupture and release the topical composition
through the tip; and contacting the tip to a targeted lesion of the
skin condition.
[0114] Some embodiments herein are directed to a kit for the
treatment of a skin condition comprising a container comprising a
compartment having hydrogen peroxide, a compartment having
2-propanol and instructions for use. Some embodiments are directed
to a kit for the treatment of a skin condition comprising a
container comprising hydrogen peroxide and 2-propanol and
instructions for use. In some embodiments, the kit further
comprises an applicator. In some embodiments, the kit may include
two or more applicators. For example, in some embodiments, a kit
may contain many applicators where there is more than one lesion to
treat (for example, in an over the counter kit or a kit for
multiple administrations by the physician) or if the kit further
includes a take home formulation of the composition for multiple
applications. In some embodiments, the kit may comprise an
applicator with a frangible glass ampoule having a solution of
hydrogen peroxide and an alcohol. In some embodiments, the kit may
comprise an applicator with a frangible glass ampoule having a
solution of hydrogen peroxide, wherein the applicator also
comprises a compartment having an alcohol, such as, without
limitation, 2-propanol, in the applicator body. In some
embodiments, the applicator may further include a compartment
having a gelling agent. In some embodiments, the kit may comprise
two or more containers of the topical hydrogen peroxide
formulation. In some embodiments, the two or more containers of the
topical hydrogen peroxide formulation may comprise hydrogen
peroxide formulations of the same hydrogen peroxide concentration.
In some embodiments, the two or more containers of the topical
hydrogen peroxide formulation may comprise hydrogen peroxide
formulations of different hydrogen peroxide concentrations. For
example, in some embodiments, the kit may comprise one 40% hydrogen
peroxide and 5% 2-propanol container for administration by the
physician in the office, and other containers of different
concentrations (e.g., weaker concentrations) of hydrogen peroxide
for the patient to take home for subsequent applications to the
target site. In some embodiments, a kit may include two or more
single-use containers of the topical hydrogen peroxide formulation
with multiple applicators. In some embodiments, a kit may include a
container having multiple dose containers of the topical hydrogen
peroxide formulation with multiple applicators. The skin condition
may be a virally induced or non-virally induced cutaneous growth or
proliferation. The skin condition may be a benign neoplasm,
premalignancy or malignancy. The skin condition may be an
inflammatory condition. The skin condition may be a
hyperproliferative condition. The skin condition may be ageing
including intrinsic and extrinsic changes (e.g., photoaging
(ultraviolet light induced changes)), pigmentary changes, fine
lines and rhytides. In some embodiments, the skin condition may be
selected from Human Papilloma Virus induced lesions e.g., warts,
common warts, palmoplantar warts, flat warts, recurrent warts,
recalcitrant warts, treatment naive warts, epidermodysplasia
verruciformis related warts, anogenital warts, condyloma
accuminatum, cervical dysplasias or neoplasias, e.g., cervical
intraepithelial neoplasia (CIN); Herpesvirus related lesions
including those induced by HHV-1 (HSV-1), HHV-2 (HSV-2), HHV-3
(varicella-zoster virus) e.g., chicken pox, Herpes zoster,
shingles; Poxvirus induced lesions e.g., molluscum contagiosum,
orf, callus, cutaneous horns, corns, acrochordons, fibroepithelial
polyps, prurigo nodularis, actinic keratoses, squamous cell
carcinoma, squamous cell carcinoma in situ, keratoacanthoma, basal
cell carcinoma, cutaneous lymphomas and benign lymphocytic
infiltrates & hyperplasias of the skin, clear cell acanthoma,
large cell acanthoma, epidermolytic acanthoma, porokeratosis,
hyperkeratosis, keratosis pilaris, lichenoid keratosis, acanthosis,
acanthosis nigricans, confluent and reticulated papillomatosis,
nevi, including e.g., dermal nevi, epidermal nevi, compound nevi,
ILVEN (inflammatory linear verrucous epidermal nevi), nevus
sebaceous, nevus comedonicus, and the like; acne, e.g., comedonal
acne, inflammatory acne, papular acne, pustular acne, cystic acne;
cysts, e.g., epidermoid cysts, milia, trichilemmal cysts,
follicular cysts, proliferating cysts, dermoid cysts, pilonidal
cysts, apocrine cysts, eccrine cysts, sebaceous cysts, mucous
cysts, myxoid cysts, ganglion cysts, synovial cysts, vellus hair
cysts, steatocystoma, hidrocystoma; adnexal neoplasms e.g.,
trichofolliculoma, fibrofolliculoma, perifollicular fibroma,
trichodiscoma, nevus sebaceous, chondroid syringoma,
trichoepithelioma, trichoblastoma, desmoplastic trichoepithelioma,
pilomatricoma, pilomatrical carcinoma, tricholemmoma, trichelemmal
carcinoma, tumor of the follicular infundibulum, tricoadenoma,
proliferating pilar tumor, sebaceous hyperplasia, sebaceous
adenoma, sebaceous epithelioma, sebaceous carcinoma, syringoma,
poroma, hidradenoma, apocrine hidradenoma, spiradenoma, cylindroma,
eccrine nevus (eccrine hamartoma), papillary adenoma, papillary
adenocarcinoma; benign melanocytic proliferations or neoplasms
e.g., ephilides, cafe-au-lait macules, Becker's melanosis,
lentigines, solar lentigines, lentigo simplex, mucosal melanocytic
lesions, Mongolian spots, Nevus of Ota, blue nevus, common acquired
melanocytic nevi (nevocellular nevus, "moles"), congenital nevi,
nevus spilus, recurrent nevi; vascular and perivascular neoplasms
and reactive hyperplasias e.g., hemangiomas, cherry angiomas,
hobnail hemangiomas (targeted hemosiderotic hemangiomas), tufted
angiomas, hemangioendotheliomas, angiolymphoid hyperplasia with
eosinophilia (ALHE), Glomus tumors (glomangiomas),
hemangiopericytomas; cutaneous neural and neuroendocrine neoplasms
e.g., neuromas, Schwannomas, neurofibromas, nerve sheath tumor,
nerve sheath myxoma, neurothekeoma, granular cell tumor; fibrotic
and fibrohistiocytic proliferations e.g., acrochordons,
fibroepithelial polyps, fibromas, fibrous papules, angiofibromas,
pearly penile papules, periungual fibromas, dermatofibromas,
fibrokeratomas, sclerotic or pleomorphic fibromas, connective
tissue nevi; cutaneous scars, hyperplasias, keloids, rosacea,
cutaneous fungal, dermatophyte & mold infections,
onychomycosis, hyperpigmentation, rhytides, psoriasis, malignant
melanoma, seborrheic keratosis, seborrheic keratosis variants
including e.g., dermatosis papulosis nigra, inverted follicular
keratosis/keratoma warty dyskeratosis/warty dyskeratoma,
acrokeratosis verruciformis, stucco keratosis; or a combination
thereof. In some embodiments, the applicator may be selected from a
sponge, a swab, a foam tipped stick, a cotton ball, a brush, a
woven or non-woven fabric, roller, gauze, a pen, or the like. In
some embodiments, the applicator is flocked, absorbent, and/or firm
enough to apply pressure to the lesion. In some embodiments the
applicator is a sintered polymeric-tip applicator. In some
embodiments, the applicator is resistant to, compatible with, or
inert to high concentration peroxide solutions. In some
embodiments, the applicator is capable of dispensing the solution
at a controlled rate in order to help confine the active to the
lesion of interest and spare surrounding normal skin. In some
embodiments, the solution may be administered using a device having
the hydrogen peroxide solution in a compartment that dispenses the
solution onto or through an applicator tip when needed. In some
embodiments, the applicator may comprise a material designed to
abrade the skin lesion or treatment site before or at the time of
administration of the composition. In some embodiments, the
applicator is a doe footed applicator. In some embodiments, the
applicator is a flocked, doe footed applicator. In some
embodiments, the flocked, doe footed applicator is comprised of
HDPE (high density polyethylene), LDPE (low density polyethylene),
Nylon, an adhesive, or any combination thereof. In some
embodiments, the container may be selected from a vial, an ampule,
a jar, a bottle, a medication tube, a syringe, or any other
container for storing liquids. In some embodiments, the compartment
may be selected from a vial, a tube, an ampoule, a jar, a bottle, a
medication tube, a syringe, or any other container for storing
liquids. In some embodiments the container may be glass,
borosilicate glass, Type I borosilicate glass, tinted or otherwise
light protected glass, amber tinted glass, amber Type I
borosilicate glass, HDPE, Teflon.RTM., silicone, ABS
(acrylonitrilebutadiene stylene), or other compatible polymer or
material. In some embodiments, the kit may include a glass vial or
bottle having a solution of hydrogen peroxide and an alcohol
disposed therein. In some embodiments the glass vial or bottle may
include an amber glass vial or bottle. In some embodiments, the kit
may comprise a vial or bottle at least partially formed from HDPE
having a solution of hydrogen peroxide and an alcohol disposed
therein. In some embodiments, the container may be formed from a
material that has a low reactivity with peroxide. In some
embodiments, the compartment may include a material that has a low
reactivity with peroxide. In some embodiments, the hydrogen
peroxide is a stabilized hydrogen peroxide. In some embodiments,
the alcohol, such as, without limitation, 2-propanol, is in an
amount of less than about 25%. In some embodiments, the kit may be
for use by a health care provider. In some embodiments, the kit may
be for use by the subject in need thereof. In some embodiments, the
kit may be available only with a prescription. In some embodiments,
the kit may be available over the counter for use by the subject in
need thereof.
[0115] FIG. 12 depicts an illustrative applicator configured
according to a first embodiment. As shown in FIG. 12, the
applicator 1200 may include an applicator body 1205. In some
embodiments, the applicator tube 1205 may be enclosed at a distal
end thereof by an end cap 1215. In some embodiments, the applicator
body 1205 and/or the end cap 1215 may be formed from various
flexible materials, including, without limitation, flexible polymer
materials. Non-limiting examples of flexible polymer materials may
include polypropylene (PP), high-density polyethylene (HDPE) or
low-density polyethylene (LDPE), polyvinyl chloride (PVC),
polyethylene (PE), derivatives thereof, and any combination
thereof. In some embodiments, the applicator body 1205 may have a
generally longitudinal shape. In some embodiments, the applicator
body 1205 may have a generally cylindrical shape. The applicator
body 1205 may have various lengths according to some embodiments,
including about 80 millimeters, about 90 millimeters, about 98
millimeters, about 99 millimeters, about 100 millimeters, about 110
millimeters, about 120 millimeters, about 130 millimeters, about
140 millimeters, about 150 millimeters, about 80 millimeters to
about 100 millimeters, about 80 millimeters to about 150
millimeters, about 90 millimeters to about 100 millimeters, about
100 millimeters to about 120 millimeters, about 100 millimeters to
about 150 millimeters, and any values or ranges between any of
these values (including endpoints). The applicator body 1205 may
have various outer dimensions according to some embodiments,
including about 5 millimeters, about 7 millimeters, about 9
millimeters, about 10 millimeters, about 12 millimeters, about 15
millimeters, about 18 millimeters, about 20 millimeters, about 5
millimeters to about 7 millimeters, about 5 millimeters to about 10
millimeters, about 7 millimeters to about 10 millimeters, about 9
millimeters to about 15 millimeters, about 10 millimeters to about
15 millimeters, about 5 millimeters to about 20 millimeters, about
10 millimeters to about 20 millimeters, and any values or ranges
between any of these values (including endpoints).
[0116] In some embodiments, an ampoule 1210 configured to store
compositions of embodiments herein may be arranged within a cavity
formed within the applicator body 1205. In some embodiments, the
ampoule 1210 may be frangible, for example, configured to shatter,
fragment, rupture, fracture, or otherwise break apart responsive to
the application of sufficient pressure thereto. For instance,
sufficient pressure may be applied manually, such as by applying a
force by a human hand (for example, by squeezing or pressing) on
the applicator body 1205 in a direction toward the ampoule 1210 in
an area of the applicator body where the ampoule is located. In
this manner, the force applied to the applicator body 1205 may be
transferred to the ampoule 1210 and the ampoule may break apart
responsive to the application of sufficient force thereto. In some
embodiments, the ampoule 1210 may be formed from various frangible
materials, including glass, plastic, a polymer material,
borosilicate glass, Type I borosilicate glass, tinted glass, and
any combination thereof. In some embodiments, the ampoule 1210 may
include one or more weakened regions to facilitate breakage of the
ampoule 1210. In some embodiments, the compositions of embodiments
herein may be caustic and/or may react with the materials of the
applicator 1200 or the environment. In some embodiments, the
compositions of embodiments herein may be degraded or otherwise
effected by contaminants and/or contact with the environment.
Accordingly, storage of compositions of embodiments herein using
one or more ampoules 1210 may protect the applicator 1200 materials
and/or the compositions of embodiments herein from being degraded
until they are released from the ampoule. Through the use of the
ampoules 1210, the applicator 1200 may, among other things, allow
for the safe and stable storage of compositions of embodiments
herein and other components until delivery is required.
[0117] The compositions of embodiments herein stored within the
ampoule 1210 may be released within the applicator body 1205
responsive to the fracturing of the ampoule 1210. The ampoule 1210
may be configured to hold various volumes of the compositions of
embodiments herein, including, about 0.1 milliliters, about 0.2
milliliters, about 0.5 milliliters, about 1 milliliters, about 1.5
milliliters, about 2 milliliters, about 2.4 milliliters, about 3
milliliters, about 3.2 milliliters, about 4 milliliters, about 5
milliliters, about 10 milliliters, about 20 milliliters, about 30
milliliters, about 50 milliliters, about 100 milliliters, about 500
milliliters, about 0.1 milliliters to about 3 milliliters, about
0.1 milliliters to about 4 milliliters, about 0.1 milliliters to
about 5 milliliters, about 0.1 milliliters to about 10 milliliters,
about 0.1 milliliters to about 100 milliliters, about 0.1
milliliters to about 500 milliliters, about 1 milliliters to about
3 milliliters, about 1 milliliters to about 4 milliliters, about 1
milliliters to about 5 milliliters, about 1 milliliters to about
100 milliliters, about 1 milliliters to about 500 milliliters,
about 2 milliliters to about 3 milliliters, about 2 milliliters to
about 4 milliliters, about 2 milliliters to about 5 milliliters,
about 2 milliliters to about 10 milliliters, about 3 milliliters to
about 4 milliliters, about 3 milliliters to about 5 milliliters,
about 3 milliliters to about 10 milliliters, about 3 milliliters to
about 100 milliliters, about 4 milliliters to about 5 milliliters,
about 4 milliliters to about 10 milliliters, about 4 milliliters to
about 100 milliliters, about 5 milliliters to about 10 milliliters,
about 5 milliliters to about 100 milliliters, about 100 milliliters
to about 500 milliliters, and any values or ranges between any of
these values (including endpoints). In some embodiments, the
ampoule 1210 may be configured to hold an effective dose of the
compositions of embodiments herein. In some embodiments, the
ampoule 1210 may be configured to hold an effective dose of the
compositions of embodiments herein sufficient to treat a single
target lesion or skin area. In some embodiments, the ampoule 1210
may be configured to hold an effective dose of the compositions of
embodiments herein sufficient to treat multiple target lesions or
skin areas. In some embodiments, an effective dose may be from
about 0.0025 milliliters to about 3 milliliters of the compositions
of embodiments herein, including about 0.0025 milliliters, about
0.01 milliliters, about 0.025 milliliters, about 0.05 milliliters,
about 0.075 milliliters, about 0.1 milliliters, about 0.15
milliliters, about 0.5 milliliters, about 1 milliliters, about 1.5
milliliters, about 2 millimeters, about 2.5 milliliters, about 3
milliliters, a combination thereof, or any amount that has a
clinical effect on the lesion. In some embodiments, the effective
dose is proportional to size of the lesion. In some embodiments,
the effective dose of the composition is less than about 0.1
milliliters per lesion. In some embodiments, an effective dose may
be about 3 milliliters of the compositions of embodiments herein.
In some embodiments, an effective dose may be from about 2
milliliters to about 3 milliliters of the compositions of
embodiments herein. In some embodiments, an effective dose may be
from about 2 milliliters to about 5 milliliters of the compositions
of embodiments herein.
[0118] Although only one ampoule 1210 is depicted in FIG. 12,
embodiments are not so limited, as the applicator 1200 may include
a plurality of ampoules. For instance, an applicator 1200 may
include multiple ampoules 1210 for multiple doses of the
compositions of embodiments herein. In another instance, an
applicator 1200 may include a plurality of ampoules 1210 housing
different compositions. In some embodiments, the applicator 1200
may include a compartment (not shown) housing a first composition
(e.g., a gelling agent, hydrogen peroxide) and one or more ampoules
1210 housing one or more second compositions (e.g., 2-propanol,
compositions of embodiments herein). For example, one or more walls
may partition the applicator body into one or more compartment
portions. In some embodiments, a compartment or a portion thereof
(e.g., a wall portion forming the compartment within the applicator
body 1205) may be fractured by the application of sufficient force
to the compartment. In some embodiments, one or more first
compositions may be disposed within the applicator body 1205 such
that one or more second compositions disposed within the one or
more ampoules 1210 and/or one or more compartments may contact the
one or more second compositions responsive to the release of the
one or more second compositions. A non-limiting example of a first
composition may include an alcohol (e.g., 2-propanol) or a gelling
agent and a non-limiting example of a second composition may
include a caustic formulation, such as a hydrogen peroxide
solution. In some embodiments, the various compositions (e.g., the
one or more first compositions and the one or more second
compositions) may be mixed together before or concurrently with the
application thereof.
[0119] In some embodiments, an applicator hub 1225 may be in fluid
communication with the applicator body 1205 at a proximal end of
the applicator 1200. The applicator hub 1225 may be configured to
receive the compositions of embodiments herein that flow from the
applicator body 1205 responsive to the release of the compositions
of embodiments herein from the ampoule 1210. In some embodiments,
at least a portion of the applicator hub 1225 may be arranged
within the applicator body 1205. In some embodiments, the
applicator hub 1225 may be fixedly attached to the applicator body
1205, such as through the use of adhesives, a friction fit, a
press-fit, a threaded fit, or the like. In some embodiments, an
outer portion of the applicator hub 1225 may be fixedly attached to
an inner portion of the proximal end of the applicator body 1205.
In some embodiments, the applicator hub 1225 may form a hermetic
seal with the applicator body 1205 through a friction fit,
adhesives, a threaded fit, or the like. In some embodiments, the
applicator hub 1225 may be formed from a polymer material,
including, without limitation, PE, PP, HDPE, and LDPE. In some
embodiments, a protective cap 1235 may be configured to enclose the
applicator hub 1225 at a proximal end of the applicator 1200.
[0120] In some embodiments, a filter 1220 may be arranged within
the applicator 1200 between the ampoule 1210 and the proximal end
of the applicator 1200. In some embodiments, the filter 1220 may be
arranged within a distal portion of the applicator hub 1225 that
faces the ampoule 1210. The filter 1220 may be configured to filter
out pieces of the broken ampoule 1210 while allowing the
compositions of embodiments herein to flow therethrough. The filter
1220 may be formed from various materials, including any material
capable of filtering out the shards of the ampoule from the
compositions of embodiments herein. Non-limiting examples of filter
1220 materials may include various polymer materials, PE, PP, HDPE,
LDPE, polystyrene (PS), carbon, a foam material, ceramic, sand,
diatomaceous earth (DE), paper fibers, and any combination thereof.
In some embodiments, the filter 1220 material may be selected to
provide a particular flow rate of the compositions of embodiments
herein through the filter.
[0121] In some embodiments, the applicator 1200 may include a tip
1230 arranged at a proximal portion thereof. In some embodiments,
the tip 1230 may be fixedly arranged within a central bore of the
applicator hub 1225. The tip 1230 may be configured to facilitate
the application of the compositions of embodiments herein onto the
skin of a patient. In some embodiments, the tip 1230 may be formed
from an absorbent or substantially absorbent material. In some
embodiments, the tip 1230 may be configured as a sintered polymeric
tip. In some embodiments, the tip 1230 may be configured as a doe
footed tip. In some embodiments, the tip 1230 may be configured as
a flocked tip, for example, that may include and/or may be formed
from a flocked material, including, without limitation flock formed
from filaments of various materials. In some embodiments, the
flocked tip may be formed by affixing a flocked material to the tip
1230. In some embodiments, the tip 1230 may be formed from various
materials that are non-reactive or otherwise chemically compatible
with the compositions of embodiments herein. In some embodiments,
the tip 1230 may be formed from various biocompatible materials. In
some embodiments, the tip 1230 may be formed from various
materials, including, without limitation, cellulose, nylon, rayon,
polyester, Teflon.RTM., fibers thereof, flocked materials thereof,
and any combination thereof.
[0122] In some embodiments, the tip 1230 may be fixedly arranged
within the applicator 1200, such as in the applicator hub 1225,
such as through adhesives, a friction fit, a threaded fit, a snap
or lock fit, a press-fit, or the like. In some embodiments, the
applicator 1200 may be configured to allow replacement of the tip
1230 during or after each use. In some embodiments, the ampoule
1210 may be replaced within the applicator 1200. For instance, an
operator may remove the end cap 1215, remove the shards of a
fractured ampoule 1210, and insert a new ampoule with the same
and/or different compositions of embodiments herein. In this
manner, the applicator 1200 may be used multiple times and/or for
the treatment of multiple skin conditions (i.e., separate lesions,
warts, or other skin formations) of the same patient. In some
embodiments, the applicator 1200 may be a single use applicator. In
some embodiments, the single use applicator is intended to be
discarded after a single use.
[0123] In some embodiments, the compositions of embodiments herein
may be released from the ampoule 1210 and flow through the
applicator body 1205 (including any chambers thereof), the filter
1220, the applicator hub 1225, and out of the applicator through
the tip 1230. In some embodiments, the applicator body 1205 and/or
the tip 1230 may be configured to allow an operator to control the
flow of the caustic formulation out of the applicator 1200. In a
non-limiting example, after the compositions of embodiments herein
have been released from the ampoule 1210, an operator may initiate
flow of the compositions of embodiments herein out of the
applicator 1200 by squeezing on the applicator body 1205, thereby
generating sufficient pressure therein to force the compositions of
embodiments herein to flow out through the tip 1230. In some
embodiments, pressing the tip 1230 on the skin of a patient may
produce capillary action sufficient to cause the compositions of
embodiments herein that have been released from the ampoule 1210
and are in contact with the tip to flow through the tip and out of
the applicator 1200. In some embodiments, an operator may control
the rate of the flow by varying a level of force used to squeeze
the sides of the applicator body 1205 and/or press the tip 1230
against the skin of the patient. In some embodiments, the
applicator 1200 may include an actuator (not shown) configured to
cause the compositions of embodiments herein to be dispensed from
the applicator.
[0124] In some embodiments, at least one portion of the applicator
may include a hydrophobic material, such as the filter 1220 and/or
the tip 1230. In some embodiments the hydrophobic material is
composed of polyester or co-polyester polymers, acrylic, modified
acrylic (e.g., modacrylic), polypropylene, polyethylene or
combinations or mixtures thereof. In some embodiments, for example,
the filter may comprise a blend of polypropylene and polyester or
co-polyester polymers. Non-limiting examples of hydrophobic
materials may also include materials including, coated with, and/or
modified by silanes, alkylsilanes, fluoroalkylsilanes, silicone,
combinations thereof, and derivatives thereof. In some embodiments,
materials used to form the applicator and portions thereof
according to some embodiments described herein may be imparted with
hydrophobic properties by coating or otherwise incorporating a
hydrophobic material therein. In some embodiments, the hydrophobic
portions of the applicator may operate to impede, reduce, prevent,
and/or substantially prevent the compositions of embodiments herein
that have been released from the ampoule from flowing through
portions of the applicator and/or out of the tip of the
applicator.
[0125] In some embodiments, the applicator 1200 may be configured
such that the compositions of embodiments herein released from the
ampoule 1210 may not be passively dispensed from the applicator
1200 without an operator applying pressure to the applicator, such
as by squeezing or otherwise applying a force to the applicator
body 1205. In some embodiments, the requirement for operator action
(i.e., applying pressure to the applicator 1200) may be facilitated
by the use of hydrophobic materials according to some embodiments.
In some embodiments, the applicator 1200 may be configured such
that a void may be formed within the applicator body 1205 behind a
volume of the compositions of embodiments herein released from the
ampoule 1210, for instance, when the applicator is orientated in a
vertical, substantially vertical, or partially vertical position.
In some embodiments, the void may operate as a vacuum to impede,
reduce, restrict, prevent, and/or substantially prevent the flow of
the compositions of embodiments herein released from the ampoule
1210 out of the applicator 1200. In this manner, the hydrophobic
portion of the applicator 1200 and/or a void formed within the
applicator body 1205 may operate to prevent the leakage of the
compositions of embodiments herein from the applicator after the
compositions of embodiments herein have been released from the
frangible ampoule 1210, including when the applicator is in a
position conducive to dispensing compositions of embodiments
herein, such as a vertical or substantially vertical position.
[0126] The applicator 1200 may be configured to store, dispense,
and apply any of the compositions of embodiments herein as part of
a method of treatment for any of the conditions disclosed herein.
For example, the applicator 1200 may be configured to store,
dispense, and apply a topical composition comprising 2-propanol and
up to about 50% hydrogen peroxide. In some embodiments, the topical
composition may be any composition described in embodiments
herein.
[0127] FIGS. 13A-13C depict a first exploded side view, a second
exploded side view, and a cross-sectional view, respectively, of an
illustrative applicator according to a second embodiment. As shown
in FIGS. 13A-13C, an applicator 1300 may include an applicator body
1305 having an ampoule 1310 arranged within an interior cavity
thereof. A proximal end of the applicator body 1305 may be enclosed
by a protective cap 1325, for example, when the applicator 1300 is
not in use. A distal end of the applicator body 1305 may be
enclosed by an end cap 1315 fixedly attached thereto, such as
through adhesives, a friction fit, a snap or lock connection, or
the like. A holed flocked tip 1330 (may be arranged within at least
a portion of the applicator body 1305 at a proximal end thereof. In
some embodiments, the holed flocked tip 1330 may be formed from or
substantially from applicator hub 1225 and tip 1230 as depicted in
FIG. 12. In some embodiments, the holed flocked tip 1330 may be
fixedly attached to the applicator body 1330, such as through
adhesives, a friction fit, a threaded fit, a snap or lock fit, or
the like. In some embodiments, a filter 1335 may be arranged within
the holed flocked tip 1330.
[0128] In some embodiments, a grip 1320 may be arranged on an
exterior portion of the applicator body 1305 at a proximal end
thereof. In some embodiments, the grip 1320 may be configured to
improve the ability of the hand of an operator to hold and control
the applicator 1300. In some embodiments, the grip 1320 may be
formed from various polymer materials, including, without
limitation, a foam material, a rubber material, a plastic material,
a thermoplastic material, or other material known to those having
ordinary skill in the art, or any combination thereof. In some
embodiments, the grip 1320 may be configured to facilitate enhanced
hand positioning, increased operator comfort, decreased hand
fatigue, or the like, when using the applicator 1300. In some
embodiments, at least a portion of the grip 1320 may include a
contoured, curved, concave, or other non-flat surface configured to
facilitate precise control of the applicator 1300 by an operator.
In some embodiments, the grip 1320 may include at least one
anti-roll feature configured to reduce or prevent the rolling or
turning of the applicator 1300 in the hand of an operator during
use thereof. In some embodiments, the grip 1320 may include at
least one anti-roll feature configured to reduce or prevent the
rolling or turning of the applicator 1300 when placed on a surface,
for example, a counter, a table, an instrument stand, or the like.
In some embodiments, the grip 1320 may be over-molded onto the
exterior surface of the applicator body 1305. In some embodiments,
the grip 1320 may be configured as a separate element that may be
slid on to, or otherwise adjoined to or affixed to, the applicator
1300.
[0129] In some embodiments, a pressure area 1345 may be arranged on
the applicator body 1305. In some embodiments, the pressure area
1345 may include a marked area configured to indicate to an
operator an optimum area on the applicator tube 1305 to apply
pressure to fracture the ampoule 1310. In some embodiments, the
pressure area 1345 may be configured to receive the fingers and/or
thumb of a user to facilitate the grip of and/or the squeezing of
the applicator tube 1305 to rupture the ampoule 1310. In some
embodiments, the pressure area 1345 may include a marked area
formed from one or more raised formations. In some embodiments, the
pressure area 1345 may be formed from materials that are molded
onto an outside surface of the applicator body 1305. In some
embodiments, the pressure area 1345 may include a printed and/or
raised feature arranged on a label affixed to an outer surface of
the applicator body 1305. In some embodiments, the pressure area
1345 may be configured to concentrate pressure applied by an
operator to rupture the ampoule 1310. In some embodiments, the
pressure area 1345 may be configured to indicate a position
directly or substantially directly above one or more force
concentration elements (not shown) located within the applicator
body 1305 that are configured to concentrate pressure applied by an
operator to rupture the ampoule 1310. In some embodiments, the
force concentration elements may include one or more struts formed
from various materials, such as a plastic material. In some
embodiments, the force concentration elements are not present in
the applicator 1300. In some embodiments, finger pressure is
sufficient to rupture the ampoule 1310. In some embodiments, the
pressure area 1345 may be formed from a more flexible material than
the other portions of the applicator tube 1305 to facilitate the
transfer of pressure from the hand of an operator squeezing on the
applicator tube 1305 to the ampoule 1310. In an embodiment in which
the applicator 1300 includes a plurality of ampoules 1310 and/or
one or more compartments (not shown), the applicator may include a
plurality of pressure areas 1345 configured to indicate an optimum
area to apply pressure to fracture each compartment and/or
ampoule.
[0130] In some embodiments, the ampoule 1310 may be fixedly
arranged within the applicator body 1305. For example, in some
embodiments, the ampoule may be fixedly arranged within the
applicator body 1305 such that the ampoule does not does not move
or substantially does not move longitudinally within the applicator
body 1305 or does not move proximally beyond a certain position
within the applicator body. In some embodiments, the size and/or
shape of the ampoule 1310 may be configured to correspond with the
size and/or shape of the applicator body 1305 (for instance, an
inner dimension of the applicator body) such that the applicator
body holds the ampoule in place therein through a friction fit. In
some embodiments, the applicator body 1305 may include a varying
inner dimension such that the ampoule 1310 may only fit within a
certain portion of the applicator body. In some embodiments, the
inner surface of the applicator body 1305 may include bumps,
ridges, projections, or other structures configured to hold the
ampoule 1310 in place and/or to prevent the ampoule from moving
longitudinally within the applicator body. In some embodiments, a
support structure 1340 may be arranged within the applicator body
to hold the ampoule 1310 in place and/or to prevent the ampoule
from moving longitudinally within the applicator body 1305. In some
embodiments, the support structure 1340 may include one or more
struts or projections (e.g., ridges, bumps, or the like) arranged
within and/or formed from portions of the applicator body 1305. In
some embodiments, the support structure 1340 may be configured to
position the ampoule for breakage by an operator. For example, the
support structure 1340 may be configured to maintain the within an
area corresponding with the pressure area 1345.
[0131] In some embodiments, the applicator 1300 may include one or
more debriding elements (not shown) arranged on an exterior portion
of the applicator, such as the applicator body 1305, the end cap
1315, and/or the protective cap 1325. The one or more debriding
elements may be configured to mechanically or physically abrade,
ablate, thin, curette, destruct, remove, excise, or otherwise
debride an area of skin of a patient, such as an area of skin
having a lesion, wart, seborrheic keratosis, or other skin
formation. In some embodiments, the one or more debriding elements
may be configured to disturb the surface of, decrease the size of,
decrease the thickness of, and/or decrease the volume of a lesion
or other skin formation. In some embodiments, the one or more
debriding elements may include an abrasive element, a sharp, a tip,
a curette, or any other element and/or formation capable of
debriding or otherwise effecting a lesion or other skin formation.
In such embodiments, an operator may use the one or more debriding
elements to debride or otherwise effect a lesion or other skin
formation before, after, and/or during application of the
compositions of embodiments herein via the applicator 1300.
[0132] FIGS. 14A and 14B depict multiple views of the applicator
body according to some embodiments. As shown in the side view A of
FIG. 14A, the applicator body 1400 may include a housing 1405
having a pressure area 1445 arranged thereon. As depicted in
internal view B of FIG. 14A, the applicator body 1400 may include a
support structure 1440 arranged therein. An end cap 1415 may be
configured to be coupled, including removably coupled, to a distal
end 1420 of the applicator body 1400. FIG. 14B depicts a side view
A and a top-down view B of an applicator body having a grip
1425.
[0133] FIG. 15 depicts an illustrative end cap of an applicator
according to some embodiments. In particular, FIG. 15 depicts a
side view A, a top-down view B, and an internal side view C of an
end cap 1500. FIG. 16 depicts a holed flocked tip (or "applicator
hub") according to some embodiments. More specifically, FIG. 16
depicts an internal side view A, a side view B, and a top-down view
C of a holed flocked tip 1600. As shown in side view B of FIG. 16,
the holed flocked tip 1600 may include a flocked portion 1605 and
an injection gate portion 1610.
[0134] FIG. 17A depicts an internal side view of a protective cap
1700 according to some embodiments, including detail 1705 for the
distal portion 1710 of the protective cap. FIG. 17B depicts the
protective cap 1700 arranged on a portion of the applicator body
1710 and enclosing a tip 1720 of the applicator according to some
embodiments. FIGS. 18A and 18B depict a side view and an internal
view, respectively, of an applicator 1800 according to some
embodiments. As shown in FIG. 18A, the applicator 1800 may include
an applicator body 1805 enclosed by a protective cap 1810. FIG. 18B
depicts an internal view of a protective cap 1810 having a spine
1815 extending from an internal surface thereof. When the
protective cap 1810 is coupled to the applicator body 1805, the
spine 1815 may engage or interface with the holed flocked tip 1820.
In some embodiments, the spine 1815 may plug, block, or otherwise
close one or more holes in the holed flocked tip 1820, preventing,
for instance, fluid from exiting the holed flocked tip. While
embodiments set forth herein are described in terms of
"comprising", all of the foregoing embodiments also include
compositions and methods that consist of only the ingredients or
steps recited or consist essentially of the ingredients and steps
recited, and optionally additional ingredients or steps that do not
materially affect the basic and novel properties of the composition
or method.
[0135] This disclosure and embodiments illustrating the method and
materials used may be further understood by reference to the
following non-limiting examples.
Example 1
[0136] A seborrheic keratosis (SK) lesion on a 76 year old female
with Fitzpatrick skin type 1 was treated with a solution comprised
of 40% stabilized hydrogen peroxide and 5% 2-propanol. After
cleansing the skin with 70% 2-propanol, the hydrogen peroxide
solution was applied topically to the seborrheic keratosis lesion
using a flocked doe-foot shaped applicator. Using firm pressure and
an application technique that was appropriate for the target lesion
size, the solution was applied for approximately 20-30 seconds.
After approximately 1-2 minutes, the application process was
repeated. This sequence was repeated until 4 applications had been
performed. There was no pain or discomfort during the procedure.
Follow-up one week later revealed the SK lesion to be resolving.
Follow-up 3 weeks after treatment revealed the lesion to be
resolving, but not completely cleared. A second treatment session
identical to the first was performed 3 weeks after the first
treatment. Follow-up 5 weeks and 8 weeks after the second treatment
revealed the lesion was completely resolved with no evidence of
recurrence of the lesion and no adverse cosmetic sequlae (e.g.,
scarring or pigmentary change (hyperpigmentation or
hypopigmentation)). The subject was extremely pleased with the
results.
Example 2
[0137] A seborrheic keratosis (SK) lesion on a 65 year old female
with Fitzpatrick skin type 4 was treated with a solution comprised
of 32.5% stabilized hydrogen peroxide and 5% 2-propanol. After
cleansing of the skin with 70% 2-propanol, the solution was applied
topically to the seborrheic keratosis lesion using a flocked
doe-foot shaped applicator. Using firm pressure and an application
technique that was appropriate for the target lesion size, the
solution was applied for approximately 20-30 seconds. After
approximately 1-2 minutes, the application process was repeated.
This sequence was repeated until 4 applications had been performed.
There was no pain or discomfort during the procedure. Follow-up 3
weeks after treatment revealed the lesion to completely resolved
with no evidence of scarring or pigmentary change
(hyperpigmentation or hypopigmentation). The subject was extremely
pleased with the results. Follow-up 11 weeks after the treatment
revealed no recurrence of the lesion and no adverse cosmetic
sequlae.
Example 3
[0138] A seborrheic keratosis (SK) lesion on a 73 year old male
with Fitzpatrick skin type 3 was treated with a solution comprised
of 25% stabilized hydrogen peroxide and 5% 2-propanol. After
cleansing of the skin with 70% 2-propanol, the solution was applied
topically to the seborrheic keratosis lesion using a flocked
doe-foot shaped applicator. Using firm pressure and an application
technique that was appropriate for the target lesion size, the
solution was applied for approximately 20-30 seconds. After
approximately 1-2 minutes, the application process was repeated.
This sequence was repeated until 4 applications had been performed.
There was no pain or discomfort during the procedure. Follow-up 3
weeks after treatment revealed the lesion to be improved, but not
completely resolved. A second treatment session identical to the
first was performed 3 weeks after the first treatment. Follow-up 1
week after the second treatment session revealed the SK lesion to
be completely resolved with no evidence of scarring or pigmentary
change (hyperpigmentation or hypopigmentation). Follow-up 8 weeks
after the second treatment (11 weeks after the first treatment)
revealed no recurrence of the lesion and no adverse cosmetic
sequelae. The subject was extremely pleased with the results.
Example 4
[0139] A common wart (verruca) on the cheek of a 56 year old white
male (Fitzpatrick Type 2 skin) was treated with a solution
comprising 40% hydrogen peroxide (FMC/PeroxiChem "Super D"), and 5%
2-propanol (Spectrum Chemical USP Grade). After cleansing of the
skin with 70% 2-propanol, the solution was applied topically to the
seborrheic keratosis lesion using a flocked doe-foot shaped
applicator. Using firm pressure and an application technique that
was appropriate for the target lesion size, the solution was
applied for approximately 20-30 seconds. After approximately 1-2
minutes, the application process was repeated. This sequence was
repeated until 4 applications had been performed. There was no pain
or discomfort during the procedure. Over the next several days the
lesion evidenced superficial crusting and mild erythema (redness).
Follow-up 2 weeks after the treatment revealed the verruca to be
completely resolved with no erythema and no evidence of scarring or
pigmentary change (hyperpigmentation or hypopigmentation).
Follow-up 8 weeks after the treatment revealed no recurrence of the
lesion and no adverse cosmetic sequelae. The subject was extremely
pleased with the results.
Example 5
[0140] A randomized, double-blind, vehicle-controlled, parallel
group study was conducted with 22 subjects, to evaluate the
effectiveness of a 40% topical solution of hydrogen peroxide and 5%
2-propanol when applied once weekly (with a maximum of 4
applications) to treatment-naive common warts on the extremities
(not periungual or subungual) compared with a matching topical
solution vehicle. The treatment protocol included (1) cleansing the
target wart by rubbing with a swab/wipe wetted with 70% 2-propanol;
(2) wetting the supplied applicator with a quantity of study
medication sufficient to wet the target wart with a thin film; (3)
applying the study medication to the target wart for approximately
10 seconds using firm pressure and a circular motion; (4) absorbing
excess study medication with a clean absorbent wipe (or equivalent)
to minimize exposure to normal surrounding skin; (5) repeating the
application procedure 3 times after a waiting period of about 20
seconds after each application. After completing the third study
medication application to the target wart, the target wart was not
disturbed until all visible reaction, if any, had stopped. After
approximately 10 minutes, any remaining study medication was
absorbed and the target wart was dried without wiping or rubbing.
17 subjects completed all four weekly treatments. All subjects
tolerated the procedure well, no adverse events were reported, and
local skin reactions were reported as none or mild. While no wart
lesions were completely resolved at the conclusion of this pilot
study (4 weekly doses)--it was expected that some of the wart
lesions would show improvement, but that complete cure of the
lesions might take more than four treatments (e.g., up to 10 or up
to 30 treatments or more)--which is common with topical wart
treatments--(e.g., over-the-counter daily salicylic acid
treatments) or would require more frequent application than weekly
(e.g., twice weekly or daily)--a statistically significant
improvement in the lesions was demonstrated and the proof-of
concept was validated. Subjects showed a statistically significant
improvement in wart severity as measured by the mean Wart
Improvement Assessment score by visit (FIG. 8) and by the mean
change in baseline in the Wart Severity Assessment score by visit
(FIG. 9). FIG. 7 describes the Wart Improvement Assessment score
and Wart Severity Assessment score.
Example 6
[0141] In vitro Drug Release and in vitro Skin Permeation studies
were performed. Thirteen formulations of 40% w/w hydrogen peroxide
were prepared using a stock solution of 50% FMC/PeroxyChem "Super
D" stabilized hydrogen peroxide as the peroxide source, with
different levels of 1 and 2-propanol for assessment--as indicated
in Table 1.
TABLE-US-00001 TABLE 1 Formulation and composition of excipients (%
w/w) P1- P2- Excipient P1-20 P1-15 P1-10 P1-5 2.5 P1-1 P2-20 P2-15
P2-10 P-2-5 2.5 P2-1 Control H2O2 (50% w/w) 80.00 80.00 80.00 80.00
80.00 80.00 80.00 80.00 80.00 80.00 80.00 80.00 80.00 1-propanol
20.00 15.00 10.00 5.00 2.50 1.00 -- -- -- -- -- -- -- 2-propanol --
-- -- -- -- -- 20.00 15.00 10.00 5.00 2.50 1.00 -- Triethanolamine
To pH 3.5 Deionized water -- q.s. 100% -- q.s. 100%
[0142] An in vitro drug release study (based on SUPAC guidelines)
with the 13 formulations was performed. The receiver fluid was PBS,
the synthetic membrane was silicone (selected after preliminary
suitability studies), and sampling volume was 1 mL with 1 mL
replenished. The measurement time points were at 0 min, 0.5 hr, 1
hr, 2 hr, 4 hr, 6 hr, and 8 hr. FIG. 1 illustrates the mean
cumulative amount of hydrogen peroxide released per unit area
following application of all formulations. FIGS. 2 and 3 compare
the release of hydrogen peroxide between formulations containing 1-
and 2-propanol, respectively, demonstrating that, in general,
increasing either 1-propanol or 2-propanol content in the
formulations produces an increase in the amount of hydrogen
peroxide released across the silicone membrane.
[0143] While in general, a higher amount of hydrogen peroxide is
released following application of formulations containing
1-propanol compared to 2-propanol on a w/w basis, this trend is
most apparent in the 1-propanol formulations and in formulations of
higher concentrations of the alcohols--beginning at approximately
above 5% alcohol concentration--and observed to a much greater
degree as the alcohol concentration increases to 10%, 15% and 20%.
This effect is illustrated by FIG. 4, which shows the steady state
release of hydrogen peroxide between 0.5 h and 4 h for the
different concentrations of 1-propanol and 2-propanol and FIG. 5,
which shows the difference in steady state release of hydrogen
peroxide between formulations containing 1-propanol and 2-propanol
at levels of 5-20% w/w. For formulations containing 1-propanol,
there is an increase in the steady state release of hydrogen
peroxide (over 0.5 to 4 h) on increasing 1-propanol content,
however for formulations containing 2-propanol, the steady state
release of hydrogen peroxide appears to remain essentially constant
across the tested concentrations of 2-propanol.
[0144] Surprisingly, and importantly, this effect of the rate of
release (0.5-4 h) of hydrogen peroxide from 1-propanol formulations
being greater than corresponding 2-propanol formulations is
reversed at lower concentrations of the alcohols, e.g., below
approximately 5% alcohol, with the rate of hydrogen peroxide
release from the 2-propanol formulations at lower alcohol
concentrations (e.g., <5%) being greater than the rate of
hydrogen peroxide release from the 1-propanol containing
formulations. Therefore, in the lower range of alcohol
concentrations to be incorporated in a preferred embodiment of the
formulation, which is most desirable, as minimizing the
concentration of the alcohol to be added may minimize the potential
impurities introduced into the peroxide formulation, it is
unexpectedly discovered that 2-propanol may be preferred over
1-propanol. Without wishing to be bound by theory, it appears that
the rate of release of hydrogen peroxide at lower concentrations of
2-propanol will greater than for the 1-propanol.
Example 7
[0145] Oxidation assessment by redox potential measurement:
Assessment of oxidation (by measuring redox potential) was
performed on 13 prepared 40% w/w hydrogen peroxide formulations as
summarized in Table 1 with and without skin at t=0, 1, 6 and 24 hr
(n=3 repetitions was performed). The redox potential data of each
of the 13 formulations summarized in Table 1 above is illustrated
in FIG. 10.
[0146] While for formulations containing less than 5% w/w propanol,
the data were not statistically significant, for formulations
containing 5% to 20% w/w propanol, a higher (more positive) redox
potential was measured for formulations containing 1-propanol when
compared to 2-propanol. That is, 1-propanol, when incorporated into
hydrogen peroxide formulations in this concentration range (i.e.
40%), will have a greater propensity to be oxidized than 2-propanol
when incorporated into these same hydrogen peroxide formulations. A
similar trend is observed in the presence of skin, where the
relative redox potential between the 1-propanol and 2-propanol
containing formulations is maintained. The data for the study
investigating the redox potential of 40% w/w hydrogen peroxide
formulations containing 5% w/w 1- or 2-propanol, both with and
without skin is illustrated in FIG. 11. Thus, while it may be
theoretically expected that secondary alcohols, (e.g., 2-propanol)
are inherently less stable in high concentrations of hydrogen
peroxide than primary alcohols, this unexpected result, in fact,
demonstrates that 2-propanol is less likely to be oxidized than
1-propanol in these embodiments, and it would be preferable to
incorporate 2-propanol into these solutions.
Example 8
[0147] Surface tension analysis was performed on the 13 40%
hydrogen peroxide formulations with varying 1-propanol or
2-propanol concentrations from Table 1 at 37.degree. C. (in
duplicate) using Kruss Tensiometer and the Wilhelmy Plate
technique. Calibration of the system using deionised water showed
results within 1.0 mN/m of the literature values at 37.degree. C.
(ca. 70 mN/m). Each sample had a 30 minute run time and the result
was calculated from the mean of the last 10 readings.
[0148] Analysis of the samples was performed in duplicate at
37.+-.0.5.degree. C. using a confidence level of .+-.1.4%. Where
the obtained duplicate results were outside this range, a third
test was performed and the reported result was calculated using the
2 closest individual results. All data has been presented in Table
2 below and illustrated in FIG. 6.
TABLE-US-00002 TABLE 2 Surface Tension (mN/m) Range Formulation
Results (1st and last reading) Rounded mean P1-20 29.65 28.05-29.76
29.8 .+-. 0.4 29.86 28.03-29.88 P1-15 33.44 29.61-33.76 33.3 .+-.
0.5 33.22 29.71-33.91 P1-10 35.42 32.84-35.30 32.9 .+-. 0.5 33.03
32.79-32.96 (Tests 2 and 3) 32.80 32.64-32.84 P1-5 38.90
39.99-38.62 38.7 .+-. 0.5 38.46 38.79-38.45 P1-2.5 45.95
45.56-45.95 45.7 .+-. 0.6 45.34 46.16-45.33 P1-1 51.58 52.37-51.46
51.0 .+-. 0.7 50.35 51.76-50.24 P2-20 32.76 33.89-32.59 32.6 .+-.
0.5 32.35 34.03-32.20 P2-15 34.28 36.99-34.10 35.9 .+-. 0.5 35.76
36.99-35.59 (Tests 2 and 3) 36.11 36.94-35.96 P2-10 41.14
41.16-41.23 41.1 .+-. 0.6 41.13 40.77-41.26 P2-5 47.73 48.36-47.75
48.3 .+-. 0.7 48.95 48.61-49.12 P2-2.5 53.54 54.42-53.46 54.1 .+-.
0.8 54.66 54.88-54.66 P2-1 59.85 62.01-59.59 60.2 .+-. 0.8 61.87
62.38-61.67 (Tests 1 and 3) 60.59 62.25-60.35 Control 58.92
61.30-58.66 60.3 .+-. 0.8 60.63 65.30-60.18 (Tests 2 and 3) 59.99
65.33-59.49
[0149] The data demonstrate that, in general, incorporating either
1-propanol or 2-propanol decreases the surface tension of the
tested hydrogen peroxide formulations, and that this
surface-tension decreasing effect is roughly proportional to the
concentration of the added 1-propanol or 2-propanol. Theoretically,
from a surface-tension point of view, either might be thought to be
useful to incorporate into the embodiments disclosed herein.
[0150] However, the effect of the surface-tension reduction of
1-propanol on the peroxide formulations is more potent than that of
2-propanol such that in the preferred embodiments formulations
containing 1-propanol will have a much lower surface tension than
the corresponding 2-propanol formulations, and will be much more
likely to spread out of the area of application and off the lesion,
on to surrounding non-lesional skin thereby lowering the
effectiveness of the therapeutic and serving as a substrate for ADH
in the skin--resulting in increased irritation, erythema, and
adverse cutaneous effects irritating the surrounding skin. 40%
hydrogen peroxide was employed in this illustrative study and
examples, but by varying the concentration of the alcohol (e.g.,
2-propanol) component in other hydrogen peroxide compositions of
the embodiments described herein (e.g., in concentrations of
hydrogen peroxide of 25%, 32.5%, 40%, 42.5%), an optimal
concentration of the alcohol that will produce the optimal surface
tension reduction, achieve the desired clinical effect, and
minimize the risk of local adverse cutaneous effects may be readily
determined.
Example 9
[0151] Solutions were prepared using stabilized hydrogen peroxide
(Peroxal CG 50.RTM. Arkema, Inc.) and 2-propanol 99% (Spectrum
Chemical, USP Grade) to make a composition comprising 40%
stabilized hydrogen peroxide and 5% 2-propanol and a composition
comprising 25% stabilized hydrogen peroxide and 5% 2-propanol. The
solutions were placed on stability in Type I amber borosilicate
glass screw-top vials and maintained at 25.degree. C./60% relative
humidity (RH); 40.degree. C./75% RH; and 5.degree. C.
(refrigerated). The 25% stabilized H.sub.2O.sub.2/5% IPA solutions
remained stable ("in specification" according to ICH Harmonised
Tripartite Guideline: Stability Testing of New Drug Substances and
Products Q1A(R2)", current Step 4 version, dated 6 Feb. 2003) under
the 40.degree. C. conditions at 6 months, and under both the
25.degree. C. conditions and 5.degree. C. conditions at 24 months.
The 40% stabilized H.sub.2O.sub.2/5% IPA solutions remained stable
("in specification" according to ICH Harmonised Tripartite
Guideline: Stability Testing of New Drug Substances and Products
Q1A(R2)", current Step 4 version, dated 6 Feb. 2003) under the
40.degree. C. conditions at 6 months, under both the 25.degree. C.
conditions and 5.degree. C. conditions at 24 months.
Example 10
[0152] Solutions were prepared using stabilized hydrogen peroxide
(Peroxal CG 50.RTM. Arkema, Inc.) and 2-propanol 99% (Spectrum
Chemical, USP Grade) to make a composition comprising 40%
stabilized hydrogen peroxide and 15% 2-propanol and a composition
comprising 25% stabilized hydrogen peroxide and 15% 2-propanol. The
solutions were placed on stability in Type I amber borosilicate
glass screw-top vials and maintained at 25.degree. C./60% relative
humidity (RH); 40.degree. C./75% RH; and 5.degree. C.
(refrigerated). The 25% stabilized H.sub.2O.sub.2/15% IPA solutions
remained stable ("in specification" according to ICH Harmonised
Tripartite Guideline: Stability Testing of New Drug Substances and
Products Q1A(R2)", current Step 4 version, dated 6 Feb. 2003) under
the 40.degree. C. conditions at 6 months, and under both the
5.degree. C. and 25.degree. C. conditions at 24 months. The 40%
stabilized H.sub.2O.sub.2/15% IPA solutions remained stable ("in
specification" according to ICH Harmonised Tripartite Guideline:
Stability Testing of New Drug Substances and Products Q1A(R2)",
current Step 4 version, dated 6 Feb. 2003) under the 40.degree. C.
conditions at 6 months, and under both the 5.degree. C. and
25.degree. C. conditions at 24 months.
Example 11
[0153] Solutions were prepared using stabilized hydrogen peroxide
(FMC/PeroxyChem "Super D 50%" (FMC/PeroxyChem) and 2-propanol 99%
(Spectrum Chemical, USP Grade) to make a composition comprising 45%
stabilized hydrogen peroxide and 5% 2-propanol. The solutions were
placed on stability in Type 1 amber borosilicate glass vials in
stability chambers and maintained at 25.degree. C./60% relative
humidity (RH), 40.degree. C./75% RH, and 5.degree. C.
(refrigerated). The 45% stabilized H.sub.2O.sub.2/5% IPA solutions
remained stable ("in specification" according to ICH Harmonised
Tripartite Guideline: Stability Testing of New Drug Substances and
Products Q1A(R2)", current Step 4 version, dated 6 Feb. 2003) under
the under the 40.degree. C. conditions at 6 months, and under both
the 5.degree. C. and 25.degree. C. conditions at 12 months.
Example 12
[0154] Solutions were prepared using stabilized hydrogen peroxide
(FMC/PeroxyChem "Super D 50%" (FMC/PeroxyChem) and 2-propanol 99%
(Spectrum Chemical, USP Grade) to make a composition comprising 40%
stabilized hydrogen peroxide and 5% 2-propanol. The solutions were
aliquoted into heat-sealed crushable glass ampules. The
solutions/ampules were placed on stability in chambers and
maintained at 25.degree. C./60% relative humidity (RH); 40.degree.
C./75% RH; and 5.degree. C. (refrigerated) conditions. The 40%
stabilized H.sub.2O.sub.2/5% IPA solutions remain stable ("in
specification" according to ICH Harmonised Tripartite Guideline:
Stability Testing of New Drug Substances and Products Q1A(R2)",
current Step 4 version, dated 6 Feb. 2003) under both the 5.degree.
C. and 25.degree. C. conditions at 12 months thus far.
Example 13
[0155] Solutions were prepared using stabilized hydrogen peroxide
(FMC/PeroxyChem "Super D 50%" (FMC/PeroxyChem, Inc.) and 2-propanol
99% (Spectrum Chemical, USP Grade) to make a composition comprising
40% stabilized hydrogen peroxide and 5% 2-propanol. The solutions
were prepared and aliquoted into amber, Type I borosilicate glass
screw-top vials. Solutions were placed on stability in chambers and
maintained at 25.degree. C./60% relative humidity (RH) and
5.degree. C. (refrigerated) conditions. The 40% stabilized
H.sub.2O.sub.2/5% IPA solutions remain stable ("in specification"
according to ICH Harmonised Tripartite Guideline: Stability Testing
of New Drug Substances and Products Q1A(R2)", current Step 4
version, dated 6 Feb. 2003) under both the 25.degree. C. conditions
and 5.degree. C. conditions at 12 months thus far.
Example 14
[0156] The following formulations were prepared using stabilized
hydrogen peroxide (Peroxal CG 50.RTM. Arkema, Inc.), 2-propanol 99%
(Spectrum Chemical, USP Grade) comprising about 44% to about 46%
(w/w) stabilized hydrogen peroxide, 0% or 5% 2-propanol (as
indicated in TABLE 3) and a gelling agent comprising either
Carbopol ETD 2020, Carbopol 974P, or Carbopol Ultrez 10, in a
concentration as indicated in TABLE 3. Disodium EDTA was also
incorporated into all formulations as a chelating agent, and pH was
adjusted to between about pH 3.5-about pH 4.0. In order to maximize
the level of hydrogen peroxide in the gel formulations, the pH
adjustment step (using 1% and 10% triethylamine) was performed
after the formulations were prepared and therefore the composition
(% weight-for-weight) in Table 3 is represented as the actual
concentration of the formulations placed on stability.
TABLE-US-00003 TABLE 3 Gel Formulations Hydrogen Peroxide Gelling
Agent 2-propanol 45.91% 0.48% w/w Carbopol ETD 0% 2020 46.11% 0.48%
w/w Carbopol 974 P 0% 45.23% 0.47% w/w Carbopol Ultrez 10 0% 44.29%
0.49% w/w Carbopol 974 P 5%
[0157] The formulations were placed on stability in chambers and
maintained at 25.degree. C./60% relative humidity (RH); 40.degree.
C./75% RH; and 5.degree. C. (refrigerated). The stabilized hydrogen
peroxide gel formulations above were assessed for stability and
based on evaluation of hydrogen peroxide recovery, pH, and
Brookfield viscosity indicated that after t=6 weeks the Carbopol
ETD, Carbopol 974 P, and Carbopol Ultrez 10 2020 maintained their
hydrogen peroxide concentrations and their chemical & physical
stability. Stability of this length of time is sufficient stability
for a two-part gel formulation (or three or more part formulation
with additional excipients such as IPA) mixed at or immediately
before the time of application where, e.g., the hydrogen peroxide
and the gelling agent are kept in separate compartments (e.g.,
separated by a frangible, in separate vials, separate syringes) and
combined or mixed when needed.
Example 15
[0158] A randomized, double-blind, vehicle-controlled,
within-subject comparison study of the safety, tolerability and
effectiveness of hydrogen peroxide/2-propanol solutions in subjects
with seborrheic keratosis was conducted. The main objective of this
study was to evaluate the effectiveness of three different hydrogen
peroxide/5% 2-propanol solutions (25% H.sub.2O.sub.2, 32.5%
H.sub.2O.sub.2, and 40% H.sub.2O.sub.2) when applied to seborrheic
keratosis (SK) target lesions on the back compared with a matching
Vehicle. Secondary objectives included evaluating the safety and
tolerability of the active solutions when applied topically in
subjects with SK. Thirty-two subjects completed the study and were
included in efficacy analyses. Subjects all had stable, clinically
typical SKs, with at appropriate SK target lesions on the back.
[0159] Subjects were randomized to study medication (a unique study
medication for each target lesion) and the study medications were
applied to the assigned target lesions, each target lesion treated
with a different study medication at Day 1. At follow-up 3 weeks
after initial medication application, any target lesion that was
not completely resolved received a retreatment study medication
application. Subjects were followed up to evaluate treatment
effects for a total of 78 days after the second study medication
application.
[0160] A statistically significant difference in the efficacy of
the active versus vehicle was first seen with the 40% solution
beginning at Day 29, seven days after the second treatment. The
length of the longest axis, the length of the perpendicular axis,
and the height of the target lesion all showed statistically
significant improvement compared with vehicle. All concentrations
of the formulation were generally well tolerated, with only a mild
"stinging" at the time of solution application and with mild
dose-related transient local skin reactions (e.g., edema, erythema)
at the time of application of the solution. There were no long-term
pigmentary changes observed.
Example 16
[0161] A randomized, double-blind, vehicle-controlled, parallel
group study was conducted using formulations of (i) 40% w/w
hydrogen peroxide and 5% 2-propanol, (ii) 32.5% w/w hydrogen
peroxide and 5% 2-propanol, and (iii) a vehicle solution for the
treatment of seborrheic keratosis lesions on the trunk and
extremities of patients. The main objective of this study was to
evaluate the dose-response relationship of 2 concentrations of the
hydrogen peroxide composition and its matching vehicle when applied
to SK target lesions on the trunk/extremities. A further objective
was to evaluate the safety and efficacy of 2 concentrations of the
hydrogen peroxide composition and its matching vehicle when applied
topically up to 2 times to SK target lesions on the
trunk/extremities. The investigators identified four eligible SK
target lesions on each subject. Each target lesion was treated a
maximum of two times. For each subject, the four target lesions
were all on the trunk/extremities. The skin of the patient was
first cleansed with 70% 2-propanol, and a thin film of the hydrogen
peroxide formulation was applied topically to the seborrheic
keratosis lesion(s) on the trunk/extremities using a flocked
doe-foot shaped applicator. Using firm pressure and an application
technique that was appropriate for the target lesion size (e.g.,
dab and roll the applicator on smaller lesions; rub using a
circular motion on larger lesions), the solution was applied for
approximately 20-30 seconds. The investigator took care to minimize
exposure to the surrounding normal skin. During the application
process, excess study medication was removed from the surrounding
skin using a clean absorbent wipe. The investigator ensured the
target lesion was wet with study medication at the end of the 20-30
seconds and allowed the target lesion to remain undisturbed for
approximately 1-2 minutes. This sequence was repeated up to 4 times
with a break of 1-2 minutes in between applications. Follow-up was
performed at numerous time points including 1 and 3 weeks after
treatment. If needed, a second treatment session identical to the
first was performed 3 weeks after the first treatment. Lesions were
evaluated to assess their clinical response 12 weeks after the
final treatment. One hundred sixty-nine subjects completed the
study. The primary endpoint, the mean of per-subject percentages of
target lesions judged to be clear on the PLA (Physician's Lesion
Assessment) scale at the last visit was 45.1% for the 40% w/w
hydrogen peroxide and 5% 2-propanol, and 26.8% for the 32.5% w/w
hydrogen peroxide and 5% 2-propanol, compared with 4.8% for
vehicle. A significantly greater improvement with both formulations
compared with vehicle was seen starting at the first evaluation,
with a dose response apparent at each visit. Local skin reactions
were predominantly mild. The results of this study confirmed that
the topical application of both the 40% H.sub.2O.sub.2 and 32.5%
H.sub.2O.sub.2 solutions to SK lesions using the prescribed method,
and formulations has the potential to safely and effectively
resolve SK lesions without the need for analgesia and/or
anesthesia, and with a minimal risk of hypopigmentation,
hyperpigmentation, or scarring.
Example 17
[0162] A randomized, double-blind, vehicle-controlled, parallel
group study was conducted using formulations of (i) 40% w/w
hydrogen peroxide and 5% 2-propanol, (ii) 32.5% w/w hydrogen
peroxide and 5% 2-propanol, and (iii) a solution vehicle for the
treatment of seborrheic keratosis lesions on the face of patients.
The main objective of this study was to evaluate the dose-response
relationship of two concentrations of the hydrogen peroxide
composition and its matching vehicle when applied to SK target
lesions on the face. A further objective was to evaluate the safety
and efficacy of two concentrations of the hydrogen peroxide
composition and its matching vehicle when applied topically up to
two times to SK target lesions on the face. The investigator
identified one eligible SK target lesions on each subject's face.
The target lesion was treated a maximum of two times. An oil based
protectant (such as 100% white petrolatum) was optionally applied
along the orbital rim and at the medial and lateral canthi; gently
stretch the periorbital skin between the thumb and forefinger at
the time of petrolatum application to distend any periorbital
rhytides (e.g., "crow's feet") and ensure full coverage of the skin
at the base of the rhytides to decrease the likelihood of tracking
of the study medication towards the eye. The subject was
additionally instructed to hold an absorbent pad in the appropriate
area of the eye to absorb any excess study medication that might
track away from the target lesion and to keep both eyes closed
during the entire study medication application procedure. The skin
of the patient was first cleansed with 70% 2-propanol, and a thin
film of the hydrogen peroxide formulation was applied topically to
the seborrheic keratosis lesion(s) on the patient's face using a
flocked doe-foot shaped applicator. Using firm pressure and an
application technique that was appropriate for the target lesion
size (e.g., dab and roll the applicator on smaller lesions; rub
using a circular motion on larger lesions), the solution was
applied for approximately 20-30 seconds. The investigator took care
to minimize exposure to the surrounding normal skin. During the
application process, excess study medication was removed from the
surrounding skin using a clean absorbent wipe. The investigator
ensured the target lesion was wet with study medication at the end
of the 20-30 seconds and allowed the target lesion to remain
undisturbed for approximately 60 seconds. This sequence was
repeated up to 4 times with a break of 1-2 minutes in between
applications. Follow-up was at several time points including 3
weeks after treatment. If needed, a second treatment session
identical to the first was performed 3 weeks after the first
treatment. Lesions were evaluated to assess their clinical response
12 weeks after the final treatment. One hundred sixteen subjects
completed the study. The primary endpoint was a pairwise comparison
between the vehicle and each active medication group based on mean
change from baseline in PLA (Physician's Lesion Assessment) score
at each post-baseline visit using ANCOVA. A significantly greater
improvement with both formulations compared with vehicle was seen
starting at the first evaluation, with a dose response apparent at
each visit. Local skin reactions were predominantly mild. The
results of this study confirmed that the topical application of
both the 40% H.sub.2O.sub.2 and 32.5% H.sub.2O.sub.2 solutions to
SK lesions on the face using the prescribed method and formulations
has the potential to safely and effectively resolve SK lesions
without the need for analgesia and/or anesthesia, and with a
minimal risk of hypopigmentation, hyperpigmentation, or
scarring.
Example 18
[0163] A 60 year old white male with Fitzpatrick Type III skin had
applications of a topical solution comprising 40% H2O2 and 5% IPA
to a clinically typical appearing ovoid seborrheic keratosis in the
right temporal area measuring 18.7.times.24.0 mm in size. Prior to
commencing the application of the solution, petroleum jelly was
applied with a cotton-tipped applicator to the area surrounding the
keratotic lesion in order to prevent the solution from tracking
along static and dynamic rhytides and better confine the solution
to the lesion.
[0164] The solution was applied as described: The target lesion was
thoroughly cleansed by firmly rubbing with a cotton-tipped
applicator wetted with 70% isopropyl alcohol (IPA). Care was taken
to keep the IPA and the H2O2 solution vial away from the face of
the subject. After cleansing the lesion, the applicator, a nylon
flocked doe-foot shaped applicator was wetted with a quantity of
peroxide/IPA solution study medication sufficient to wet the target
lesion with a thin film. Using medium-to-firm pressure and an
application technique that was appropriate for the target lesion
size, the solution was applied using a circular motion in an amount
sufficient to cover the entire surface of the lesion (seborrheic
keratosis) for approximately 30 seconds. Care was taken to minimize
exposure to the surrounding normal skin. During the application
process excess study medication was removed from the surrounding
skin using a clean absorbent wipe to dab away any excess. The
target lesion was then allowed to remain undisturbed for
approximately 1-2 minutes. The solution remained confined to the
area of application on the skin lesion. After the approximately 1-2
minutes, the application process was repeated until the
peroxide/IPA solution had been applied to the target lesion a total
of 4 times.
[0165] The procedure was well tolerated and without complications.
The maximal discomfort was described as a "stinging" that peaked at
"about 1" (mild) on a 5-point scale (0-4). At the conclusion of the
application session, the area demonstrated a "superficial
whitening" reaction that extended over only the area of application
of the solution, with minimal accompanying erythema. No solution
ran-off the lesion and there was no whitening or any adverse effect
outside the area of application. Upon questioning approximately 20
minutes following the last application, the discomfort was noted to
have already completely resolved (was rated at "0/4). Evaluation
about 75 minutes after the last application revealed almost
complete resolution of the "superficial whitening" reaction.
[0166] Over the next several days, superficial crusting developed
over the treated area and over the next several weeks the lesion
sloughed off without complication. Follow-up 38 days after the
initial application revealed the treatment area to be completely
healed with near complete resolution of the original treated
lesion, but for a small area at the inferior edge of the prior
application site. The area was again treated at that time using the
method outlined above, with the same procedure, same response, and
no complications. Superficial crusting again developed over the
treated area, which resolved within "about a week" according to the
subject. A follow-up 31 days after the second application revealed
complete resolution of the lesion with outstanding cosmesis. The
subject was extremely pleased with the results. A long-term
follow-up 193 days after the first application (155 days after the
second application) revealed no recurrence of the original SK
lesion and that the outstanding cosmesis was maintained.
Example 19
[0167] A vehicle-controlled, within subject study of the
bioavailability of a hydrogen peroxide and 2-propanol topical
solution administered under maximal use conditions in subjects with
clinically typical seborrheic keratosis on the back will be
undertaken. The main objective of this study will be to assess the
relative bioavailability of a solution of 40% hydrogen peroxide/5%
2-propanol when administered topically under conditions of maximum
use in subjects with seborrheic keratosis (SK) on the trunk, face,
and extremities. A further objective will be to evaluate the safety
of the 40% hydrogen peroxide/5% 2-propanol solution when
administered topically under conditions of maximum use in subjects
with seborrheic keratosis on the trunk, face, and extremities. It
is expected that each subject will have 10 SK target lesions on the
trunk, face, and extremities for treatment and evaluation. At least
one target lesion on each subject will be on the face. During this
study, the investigator will identify 10 eligible SK lesions on
each subject's trunk, face, and extremities. Each SK target lesion
will be treated once (first) with a solution vehicle to obtain
non-treated pharmacokinetic blood samples, and then, one week
later, with the active formulation.
[0168] Blood samples for pharmacokinetic (PK) analysis of hydrogen
peroxide will be collected at time points ranging from 0 hour (just
prior to the study medication application) to at least about 6
hours after the study medication application is completed. PK
samples will be collected at the same time of day to eliminate
complications associated with any potential diurnal variation in
endogenous hydrogen peroxide plasma levels. The investigator will
measure clinical parameters of the lesions including the lesion
dimensions (i.e., length and width) for each target lesion at Visit
1. A statistical analysis will be performed and relative
bioavailability will be calculated for the active solution compared
to vehicle solution. The statistical analysis may include an
analysis of variance (ANOVA) for the PK parameters of Cmax, AUC0-t,
and AUC0-.infin.. Data for Cmax and AUC0-t will be subject to
natural log transformation prior to analysis.
[0169] It is anticipated that the main objective of this study will
be achieved- to assess the relative bioavailability of a solution
of 40% hydrogen peroxide/5% 2-propanol when administered topically
under conditions of maximum use in subjects with seborrheic
keratosis (SK) on the trunk, face, and extremities. It is
anticipated that no measurable blood level of hydrogen peroxide
will be detected under these maximal use conditions. It is
anticipated that the further objective- to evaluate the safety of
the 40% hydrogen peroxide/5% 2-propanol solution when administered
topically under conditions of maximum use in subjects with
seborrheic keratosis on the trunk, face, and extremities will be
achieved. It is anticipated that the test solution will be found to
be safe for use when administered topically under these maximal use
conditions.
Example 20
[0170] An applicator having a topical composition solution having
40% hydrogen peroxide and 5% isopropyl alcohol disposed within a
frangible ampoule disposed in the applicator body of the applicator
is obtained for treating a patient having seborrheic keratosis
lesions on the face, trunk, and extremities. The lesion is cleansed
by rubbing with a 70% isopropyl alcohol wipe, before treatment. The
applicator is activated by depressing the exterior of the
applicator body with thumb and forefinger to break the frangible
ampule and release the solution. The applicator should be held away
from the patient while activating the package. After the applicator
is activated, the cap is removed, and the tip is wetted by gently
squeezing the exterior of the applicator body until the package tip
is wet with a quantity of solution sufficient to wet the lesion
with a thin film.
[0171] Using appropriate pressure, the solution is applied to the
lesion using a circular motion for 20 to 30 seconds. During the
application, any excess solution should be removed from surrounding
skin using a clean absorbent wipe.
[0172] The treated lesion is undisturbed for approximately 1 minute
and then the application is repeated. This can be repeated up to 4
times until the lesion(s) is completely saturated with
solution.
[0173] After completing treatment of each targeted lesion, the
lesion(s) should not be disturbed until the solution has completely
dried. The treated lesions may be dabbed, without wiping, with an
absorbent wipe to ensure the treated lesion is dry before the
patient is released.
[0174] If the lesion(s) has not completely cleared after
approximately three weeks, further treatment(s) may be applied by
following the initial procedure.
Example 21
[0175] An applicator will have an applicator body formed from HDPE,
LDPE, or an HDPE/LDPE blend, with a borosilicate glass ampoule
arranged therein. A single treatment dose of a formulation of 40%
w/w hydrogen peroxide and 5% 2-propanol will be disposed within the
ampoule. An operator will hold the applicator in their hand in a
manner similar to holding a writing utensil to write. The operator
will position an index finger on a first pressure area arranged on
an external surface of the applicator body and the opposing thumb
on a second pressure area arranged on a substantially opposite side
of the applicator body. The operator will squeeze the applicator
body using their index finger and opposing thumb with sufficient
force to rupture the ampoule arranged within the applicator body
between the first pressure area and the second pressure area. The
operator will shift the position of their hand on the applicator
down to a grip area on a proximal portion of the applicator body.
The operator will cause the formulation to be released from a nylon
flocked doe-foot shaped tip of the applicator in fluid
communication with the applicator tube by squeezing on the grip
area using their fingers.
[0176] A filter formed from LDPE that is coated with a silicone
material configured to impart hydrophobic properties to the filter
will be arranged within the applicator to filter the shards from
the ruptured ampoule. The filter will prevent the flow of the
formulation therethrough unless the operator applies pressure to
the applicator body. The operator will control a rate of flow from
the applicator onto a target application site (e.g., a skin lesion)
by varying the pressure applied to the grip area. The operator will
then treat the target lesion or lesions.
[0177] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contained within this
specification.
* * * * *